JOHN   A.  BAYCno^r 

SWC<2E€«iUM  TO 


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JOHN  A.   BAVCROF 

SUCCESSOH  TO 


ALLEN'S 

Commercial    Organic   Analysis. 


AUTHORIZED    EDITIONS. 


A  Treatise  on  the  Properties,  Proximate  Analytical  Examination  and 
Modes  of  Assaying  the  Various  Organic  Chemicals  and  Products  employed 
in  the  Arts,  Manufactures,  Medicine,  &c.,  with  Concise  Methods  for  the 
Detection  and  Determination  of  Impurities,  Adulterations  and  Products  of 
Decomposition,  &c.  Revised  and  Enlarged.  By  Alfred  Allen,  f.c.s., 
Public  Analyst  for  the  West  Riding  of  Yorkshire  and  the  City  of  Sheffield; 
Past  President  Society  of  Public  Analysts    of  England,  &c. 

Vol.  I.  Introduction.  Alcohols,  Neutral  Alcoholic  Derivatives,  &c., 
Ethers,  Vegetable  Acids,  Starch  and  its  Isomers,  Sugars,  &c.  Third 
Edition,  v^ith  numerous  additions  by  the  author,  and  revisions  and 
additions  by  Dr.  Henry  Lepfmann,  Professor  of  Chemistry  and 
Metallurgy  in  the  Pennsylvania  College  of  Dental  Surgery,  and  in 
the  Wagner  Free  Institute  of  Science,    Philadelphia,  &c.     8vo. 

Cloth,  $4.50 

Vol.  II — Part  I.  Fixed  Oils  and  Fats,  Glycerine,  Nitro-glycerin, 
Dynamite  and  Smokeless  Powders,  Wool-Fats,  D^gras,  &c.  Third 
Edition,  Revised  by  Dr.  Henry  Leffmann,  with  numerous 
additions  by  the  author.     8vo.  Cloth,  $3.50 

Vol.  II — Part  II.  Hydrocarbons,  Mineral  Oils,  Lubricants,  Asphalt, 
Benzine  and  Naphthalene,  Phenols,  Creosotes,  &c.  Third  Edition, 
Revised  by  Dr.  Henry  Leffmann,  with  many  additions  by  the 
author.  Cloth,  $3.50 

Vol.  II — Part  III.  Acid  Derivatives  of  Phenols,  Aromatic  Acids,  Resins, 
and  Essential  Oils.  Third  Edition,  Rewritten  and  Revised  by  the 
author  and  Arnold  R.  Tankard,  f.c.s.  Cloth,  $5.00 

Vol.  Ill — Part  I.  Tannins,  Dyes  and  Coloring  Matters,  Writing  Inks. 
Third  Edition,  Rewritten  and  Enlarged,  by  J.  Merritt  Matthews, 
Ph.D.,  Professor  of  Chemistry  and  Dyeing  in  the  Philadelphia 
Textile  School.  Cloth,  $4.50 

Vol.  Ill — Part  11.  The  Amines  and  Ammonium  Bases,  Hydrazines  and 
Derivatives.  Bases  from  Tar.  The  Antipyretics,  &c.  Vegetable 
Alkaloids,  Tea,  Coffee,  Cocoa,  Kola,  Cocaine,  Opium,  &c.  Second 
Edition.     With  numerous  addenda.     8vo.  Cloth,  $4.50 

Vol.  Ill— Part  III.  Vegetable  Alkaloids,  Non-Basic  Vegetable  Bitter 
Principles.  Animal  Bases,  Animal  Acids,  Cyanogen  and  its  Deriva- 
tives, &c.     Second  Edition.     8vo.  Cloth,  $4.50 

Vol.  IV.  Pvoteids  and  Albuminous  Principles.  Proteoids  or  Albu- 
minoids.    Second  Edition.  Cloth,  $4.50 


P.    BLAKISTON'S   SON    &   CO., 

Medical  and  Scientific  Publishers, 
ESTABLISHED  1843.  IOI2  WALNUT  ST.,  PHILADELPHIA. 


COMMERCIAL 

ORGANIC  ANALYSIS 


A  TREATISE  ON 

THE    PROPERTIES,   PROXIMATE    ANALYTICAL    EXAMINATION, 
.      AND    MODES    OF    ASSAYING  THE  VARIOUS    ORGANIC 
CHEMICALS    AND    PRODUCTS    EMPLOYED    IN 
THE  ARTS.  MANUFACTURES,  MEDICINE 

WITH    CONCISE    METHODS    FOR 

THE  DETECTION  AND   DETERMINATION  OF   THEIR  IMPURITIES,  ADUL- 
TERATIONS,  AND  PRODUCTS  OF  DECOMPOSITION 

ALFRED  H.  ALLEN,  F.LC,  F.C.S. 

PAST   PRESIDENT  SOCIETY   OF   PUBLIC   ANALYSTS 
PUBLIC   ANALYST   FOR   THE   WEST   RIDING  OF  YORKSHIRE,  THE   CITY   OF   SHEFFIELD,  AC. 


Second  BMtion,  IRevise^  an&  BnlaraeO 

1902    REPRINT    WITH    ADDENDA 

VOLUME  1 1 1— PART  1 1 

AMINES  AND  AMMONIUM  BASES,  HYDRAZINES,  BASES  FROM  TAR, 
VEGETABLE  ^AL,K.ALPJDS 


'  '  :l/  PrfLLADELFHlA  ^   ; -^^  ^  ^ 
P.    BLAKISTON'S    SON    &   CO 

1012   WALNUT    STREET 
1907 


JOHN   A.  BAYCROF 

SUCCESSOI?  TO 


PREFACE  TO  VOLUME  III.-PART  IL 


It  is  ten  years  since  the  publication  of  the  last  edition 
of  that  part  of  Commercial  Organic  Analysis  which 
treated  of  Alkaloids  and  Tar  Bases.  These  subjects 
then  occupied  about  120  pages.  In  the  edition  now 
issued  570  pages  have  already  been  printed,  and  I  feel 
reluctantly  compelled  to  publish  the  subject-matter 
now  ready  as  Part  II.  of  Volctme  III,  leaving  the 
sections  on  the  less  important  Alkaloids  and  the 
chapters  on  Animal  Bases,  Cyanogen  Compounds, 
Proteids,  &c.,  to  be  issued  separately  as  Part  III. 

In  Part  IL,  now  published,  I  have  endeavoured 
to  describe  fully  and  accurately  such  of  the  Organic 
Bases  as  have  any  practical  interest,  and  to  give 
reliable  information  as  to  their  sources.  The  Amines, 
Hydrazines,  and  Pyridine  and  its  Derivatives  are 
now  considered  for  the  first  time.  The  Antipyretics, 
and  other  synthetical  remedies  with  which  modern 
Chemistry  has  enriched  medicine,  are  described  fully, 
in  cases  where  they  fall  appropriately  within  the  scope 
of  the  present  Volume ;  and  I  believe  the  sections  on 
Antipyrine,  Antifebrin,  Phenacetin,  Thalline,  &c., 
contain  a  resume  of  all  published  information  on  their 
respective  subjects.  In  the  Chapter  on  Vegetable 
Alkaloids  I  have  spared  no  pains  to  render  the  more 
important  articles  as  complete  and  trustworthy  as 
possible,  and   in  this  endeavour  have  received  most 


58348 


iv  PREFACE. 

valuable  assistance  from  Mr  W.  Chattaway,  Mr  A.  J. 
Cownley,  Mr  R.  A.  Cripps,  Mr  D.  B.  Dott,  Mr  A.  W. 
Gerrard,  Mr  0.  Hehner,  Dr  B.  H.  Paul,  Mr  M.  J. 
Sheridan,  Dr  C.  R.  Alder  Wright,  and  Mr  R.  Wright, 
who  have  kindly  perused  and  corrected  some  of  the 
more  important  sections.  When  it  is  borne  in  mind 
that  the  article  on  Aconite  Bases  occupies  44  pages, 
that  on  Atropine  and  its  Allies  27,  Coca  Alkaloids  23, 
Opium  Alkaloids  Q7 ,  Cinchona  Alkaloids  79,  and  Tea 
and  Coffee  27  pages  each,  it  is  evident  that  these 
gentlemen  had  no  light  task. 

I  have  also  to  acknowledge  the  zealous  assistance  of 
Mr  G.  E.  Scott  Smith,  Mr  C.  M.  Caines,  Mr  G.  S.  A. 
Caines,  and  other  workers  in  my  laboratory,  in 
researches  on  the  Assay  of  Aconite  Bases,  the  Deter- 
mination of  Caffeine,  and  much  similar  original  experi- 
mental work,  the  results  of  which  will  be  found 
duly  recorded. 

In  the  sections  on  Tea,  Coffee,  and  Cocoa,  which 
conclude  the  Volume  and  together  occupy  73  pages, 
I  have  incorporated  nearly  every  item  of  trustworthy 
information  of  a  chemical  nature  within  my  knowledge, 
and  I  believe  these  articles  will  be  found  of  service  by 
many  besides  professional  chemists. 

Part  III.,  completing  the  work,  will  be  published 
as  soon  as  possible,  and  will,  I  hope,  be  followed  at  no 
distant  date  by  a  New  Edition  of  the  earlier  Volumes. 


ALFRED  H.  ALLEN. 


101,  Leadenhall  Street, 
London,  E.G.,  1st  October  1892. 


CONTENTS. 


AMINES  AND  AMMONIUM  BASES. 

PAGE 

( 

Classification  and  Nomenclature  of  Amines,         ...  1 

monamines, 3 

Distinction  and  Separation  of  Monamines,  4  ;  Methyl- 
amine,  9  ;  Dimethylamine,  12  ;  Trimethylamine,  12  ; 
Ethylamines,  17. 

Ammonium  Bases, 18 

Tetrethylammonium  Compounds,  19. 

HYDRAZINES. 
Hydrazine, 22 

Imidazoic  Acid,  24. 

Substituted  Hydrazines, 25 

Ethyl-hydrazine,  26;  Phenyl-hydrazine,  27;  Hydrazones,  30; 
Osazones,  30;  Pyrazolones,  30;  Antipyrine,  32. 

BASES  FROM  TAR. 
Classification  of  Tar  Bases, 39 

Aniline  and  its  Allies, 40 

Aniline,  43;  Aniline-sulphonic  Acids,  49;  Nitranilines,  50; 
Toluidines,  51;  Xylidines,  57;  Cumidines,  59;  Aniline 
Oils,  60;  Anilides,  67;  Acetanilide,  68;  Benzanilide,  72; 
Substituted  Anilines,  73;  Dimethyl-aniline,  74;  Dipheuyl- 
amine,  79;  Amido-phenols,  80;  Phenacetins,  81;  Pheny- 
lene-diamines,  86;  Benzidine,  88. 


VI  CONTENTS. 

PAGB 
Naphthylamines  and  their  Allies, 90 

o-Naphthylamine,  91  ;  )8-Naphthylamine,  92  ;  Naphthyl- 
amine-sulphonic  Acids,  92;  Naphthylene-diamines,  93; 
Amidonaphthols,  94. 

Pyridine  Bases, 96 

Pyridine,  99;  Piperidine,  106;  Homologues  of  Pyridine,  107; 
Pyridine-carboxylic  Acids,  110;  Pyrrol,  113;  lodol,  114. 

QUINOLINE  AND  ITS  ALLIES, 114 

Quinoline,  116;  Antipyretics  allied  to  Quinoline,  119;  Thai- 
line,  120;  Quinazolines,  122. 

ACRIDINE  AND  ITS  ALLIES, 123 

Acridine,  123;  Phenanthridine,  126. 


VEGETABLE  ALKALOIDS. 
Characters  and  Classification  op  Alkaloids,         ,        ,       .      127 

General  Eeactions  of  Alkaloids, 130 

Keactions  of  the  Alkaloids  with  Acids,  130;  Titration  of 
Alkaloids,  130;  Eeactions  of  the  Alkaloids  with  Alkalies, 
132 ;  Saponification  of  Alkaloids,  133 ;  General  Precipi- 
tants  of  Alkaloids,  134;  Colour-reactions  of  Alkaloids, 
144;  Physiological  Tests  for  Alkaloids,  149. 

Isolation  and  Purification  of  Alkaloids,       ....      161 

Extraction  by  Immiscible  Solvents,  154;  Dragendorff's  Method 
of  Separating  Alkaloids,  159. 

Constitution  and  Synthesis  of  Alkaloids,      ....      163 

Volatile  Bases  op  Vegetable  Origin, 170 

Conine,  171;  Assay  of  Hemlock,  176;  Lupine  Alkaloids,  178; 
Nicotine,  179;  Tobacco,  184;  Snuff,  193;  Piturine,  194; 
Lobeline,  195;  Sparteine,  197;  Spigeline,  198. 

Aconite  Bases, 198 

Constitution  and  Characters  of  the  Aconite  Bases,  201;  Aconi- 
tine,  207;  Anhydro-aconitine,  213;  Aconine,  214;  Amor- 
phous Bases,  215;  Pseudaconitine,  216;  Veratric  Acid 


CONTENTS.  VU 

PAGE 

218;  Japaconitine,  220;  Picraconitine,  221 ;  Lyaconitine, 
223;  Acolyctine,  224;  Myoctonine,  225;  Atisine,  226; 
Assay  of  Aconite  and  its  Preparations,  228;  Toxicology 
of  Aconite,  236. 

Atropine  and  its  Allies.    Tropeines, 243 

Constitution  of  Atropine  and  its  Allies,  244;  Atropine,  247; 
Hyoscyamine,  249;  Hyoscine,  250;  Atropamine,  251; 
Belladonnine,  252;  Homatropine,  253;  Detection  and 
Determination  of  Tropeines,  254;  Belladonna,  Henbane, 
and  Stramonium,  262. 

Coca  Alkaloids, 270 

Cocaine,  273  ;  Benzoyl-ecgonine,  282  ;  Ecgonine,  283  ;  Bases 
allied  to  Cocaine,  284;  Amorphous  Bases  of  Coca,  287; 
Coca  Leaves,  290. 

Opium  Alkaloids, 293 

Constitution  of  Opium  Bases,  294;  General  Characters,  300; 
Colour-reactions,  303;  Separation,  305;  Morphine,  309; 
Apomorphine,  319;  Basic  Associates  of  Morphine,  320; 
Codeine,  321;  Cryptopine,  324;  Narceine,  326;  Narcotine, 
327;  Rhoeadine,  331;  Thebaine,  331 ;  Opium,  332;  Meco- 
nin,  335;  Meconic  Acid,  336;  Adulterations  of  Opium, 
340;  Assay  of  Opium  for  Morphine,  342;  Tincture  of 
Opium,  350 ;  Compound  Tincture  of  Camphor,  353 ; 
Toxicology  of  Opium  and  Morphine,  355. 

Strtchnos  Alkaloids, 360 

Strychnine,  361;  Detection  of  Strychnine,  364;  Toxicology  of 
Strychnine,  372;  Easton's  Syrup,  376;  Vermin-killers, 
378;  Brucine,  381;  Nux  Vomica,  384;  Curare,  387. 

Cinchona  Alkaloids, 391 

Table  of  Cinchona  Bases,  392  ;  General  Properties  of  Cin- 
chona Bases,  394;  Quinine,  397;  Quinine  Sulphate,  406; 
Examination  of  Quinine  Salts,  408 ;  Citrate  of  Iron 
and  Quinine,  418;  Hydroquinine,  424;  Quinidine,  425; 
Quinamine,  427 ;  Cinchonidine,  428 ;  Cinchonine,  431  ; 
Amorphous  Cinchona  Bases,  433  ;  Alkaloids  of  Remijia 
Barks,  436;  Cupreine,  438;  Cinchona  Barks,  440; 
Assay  of  Cinchona  Barks,  449;  Separation  of  Cinchona 
Bases,  453. 


Vlll  CONTENTS. 

PAGE 

Berberine  and  its  Associates, 461 

Berberine,  461;  Oxyacanthine,  465;  Hydrastine,  467;  Calumba 
Root,  471;  Columbin,  472. 

Caffeine  and  its  Allies, 472 

Caffeine,  474;  Isolation  and  Determination  of  Calfeine,  484; 
Theobromine,  492;  Diuretin,  497;  Tea,  499;  Extract  and 
Infusion  of  Tea,  505;  Adulterations  of  Tea,  509;  Ash 
of  Tea,  510;  Tannin  in  Tea,  515;  Exhausted  Leaves  in 
Tea,  513;  Facings  of  Tea,  521 ;  Eecognition  of  Foreign 
Leaves  in  Tea,  522;  Paraguay  Tea,  526;  Coffee,  527; 
Roasting  of  Coffee,  530;  Factitious  Coffee,  535;  Chicory, 
538 ;  Adulterations  of  Coffee,  539 ;  Coffee  Extract,  553 ; 
Kola  Nuts,  554;  Guarana,  555;  Cocoa  and  Chocolate, 
555;  Cocoa  Nibs,  557;  Commercial  Cocoa,  561;  Essence 
of  Cocoa,  562;  Analysis  of  Cocoa,  564;  Cacao  Butter,  568. 


PLATES, 572 

INDEX, 573 


ADDENDA     (issued  with  the  reprint  of 

1902), 583 


AMINES  AND  AMMONIUM  BASES. 


WuRTZ,  in  1848,  pointed  out  that  one  of  the  hydrogen  atoms 
of  ammonia,  HgN,  could  be  replaced  by  ethyl,  CgHg,  and 
shortly  afterwards  A.  W.  H  o  f  m  a  n  n  proved  that  the  substitution 
by  ethyl  and  other  alkyl  radicals  could  be  extended  to  the  second 
and  third  atoms  of  hydrogen,  the  new  bodies  thus  produced  being 
powerfully  alkaline  and  in  other  respects  closely  resembling 
ammonia  itself.  H  o  f  m  a  n  n  called  these  new  bases  amines, 
and  proved  them  to  be  the  simplest  members  of  a  numerous  class 
of  synthetically  producible  compounds.  He  classified  them  as 
primary,  secondary,  and  tertiary  amines,  according 
as  one, .  two,  or  all  three  of  the  hydrogen  atoms  of  the  ammonia- 
molecule  were  replaced  by  alcoholic  or  alkyl  radicals.  As  these 
atoms  of  hydrogen  may  be,  and  very  often  are,  replaced  by  two  or 
more  different  organic  radicals,  m  i  x  e  d  amines  exist,  and  are 
capable  of  numerous  metameric  modifications.  Thus  a  base  having 
the  empirical  formula  CgH^gN  may  have  any  one  of  the  five 
following  constitutions : — 

1.  Amyl-amine, H     VN 

H    j 

C^Hc 

2.  Butyl-methyl-amine, CHg  J>  N 

H 

C3H7 

3.  Propyl- ethyl-am  ine, CgH^  J-N 

H 

C3H,) 

4.  Propyl-dimethyl-amine,    ....      CH3  >  N 

CH3J 

0.  Diethyl-methyl-amine,      ....     CgHg  I N 

CH3) 

VOL.   III.   PART  II.  A 


NOMENCLATURE  OF  AMINES. 


Of  these  raetameric  bases,^  the  first  only  is  a  primary  monamine  •, 
the  second  and  third  are  secondary  amines ;  and  the  fourth  and 
fifth  tertiary  bases.  They  could  be  distinguished  by  their  behaviour 
with  ethyl  iodide,  nitrous  acid,  and  the  other  reactions  described 
on  page  4  et  seq. 

The  hydrogen  of  ammonia  may  also  be  replaced  bj-  an  acid 
radical,  such  as  acetyl  or  benzoyl,  when  the  resultant  com- 
pound no  longer  possesses  basic  properties,  and  is  termed  an 
amide  (e.g.^  acetamide,  CgHgO.NHg).  Mixed  compounds  also 
exist,  such  as 


CH3) 

ftOVN; 


which  may  be  called  either  methyl-acetamide  or  acetyl- 
methylamine.  Bases  are  also  known  which  are  derived  from 
the  replacement  of  certain  of  the  atoms  of  hydrogen  in  two,  three, 
and  even  four  associated  molecules  of  ammonia,  the  products  being 
called  respectively  diamines,  triamines,  and  tetramines, 
which  closely  resemble  the  monamines  in  their  general  characters. 
The  following  are  examples  of  such  bases  : — 


Monamines— 

Phenylamine 
{Aniline). 

(CeHg) 
H 
H 


Diethylamine. 

(CA) 


)  (CA))  (CH3)) 

U  CA   U  (CH3)U 

3  H    )  (CHjj 


Trimethylamine. 

(CH3) 
(CH3) 
(CH3) 


Diamines — 

Phenylene-diamine. 

H„ 


Diethylene-diamine. 

(C,H,)"  U^ 
(C,HJ'j 


Triethylene-diamine. 

(C^H,)") 
(C,H/U-, 


Thiamines — 

Diethylene-triamine. 


(CA)"Pa 
(CA)"j 


Triethylene-triamine. 

H3 

(C^H,)" 
(C^H,)" 
(CA)" 


N3 


Tetramines — 

Triethylene-tetramine. 

He 

(CAV 

^  It  is  evident  that  the  formulae  in  the  text  do  not  exhaust  all  possible 
modifications  of  the  base  CgHigN,  as  they  do  not  take  into  account  the  various 
isomeric  modifications  of  which  propyl,  butyl,  and  amyl  are  susceptible. 


}"■ 


NATUKAL  AMINES.  8 

Interesting  bases  are  also  obtainable  by  the  substitution  of  organic 
radicals  for  the  hydrogen  atoms  of  H3P,  HgAs,  and  HgSb. 

The  majority  of  the  known  bodies  of  the  amine  class  are 
synthetical  compounds  of  great  scientific  but  little  practical  interest. 
Some  few  amines  have  been  found  to  exist  naturally  in  plants 
(e.g.,  trimethylamine,  conine),  and  others  are  met  with  in  animal 
fluids  (e.g.,  urea),  or  the  products  of  the  decomposition  of  animal 
matters  (leucine,  glycocine).  The  tar-bases  may  be  regarded  as 
belonging  to  the  amine  class,  aniline  and  toluidine  being 
primary,  and  pyridine  and  q  u  i  n  o  1  i  n  e  tertiary  monamines. 
Pi  peri  dine,  conine,  and  sarcocine  are  examples  of 
secondary  monamines;  while  urea  and  diamidobenzene 
may  be  regarded  as  diamines,  and  biuret  and  guanidine  as 
triamines.  Choline  and  n  e  u  r  i  n  e  are  related  to  the  tetra- 
alkyl-ammonium  bases.  The  monamines  may  be  advantageously 
considered  at  the  present  stage,  but  the  majority  of  the  amine  bases 
will  be  more  conveniently  described  in  other  chapters. 


MONAMINES. 

These  bases  are  derived  from  one  molecule  of  ammonia  by  the 
substitution  of  one  or  more  of  the  hydrogen  atoms  by  an  equivalent 
number  of  alkyl  radicals.  The  first  body  obtained  of  this  class 
was  ethylamine,  CgHg.NHg,  prepared  by  Wurtz  in  1848 
by  distilling  ethyl  cyanurate  with  caustic  potash.  Methylamine, 
CHg.NHg,  was  obtained  by  the  same  chemist  in  the  following  year, 
by  the  distillation  of  methyl  isocyanate  (acetonitrile)  with  caustic 
alkali :— 2K0H  +  CH3.N.CO  =  KgCOg  +  CH3.NH2 . 

Hofmann  obtained  the  monamines  by  the  reaction  of  an  alkyl 
iodide  on  an  alcoholic  solution  of  ammonia.  The  reaction  is 
not  a  simple  one,  all  three  monamines  being  formed  together 
with  a  tetra-alkylated  ammonium  base.  Thus,  when  ethyl  iodide 
is  heated  with  alcoholic  ammonia  to  100°  in  a  sealed  tube,  there 
are  obtained : — 

Hydriodide  of  ammonia,     .     .     .  HgNjHI  =  H^NI 

„           monoethylamine,  .  (C2Hj5)H2N,HI  =  (C2H5)H3NI 

„           diethylamine,        .  (C2H5)2HN,HI  =  (C2H5)2H2NI 

triethylamine,        .  (C2H5)3N,HI  =  (C2H5)3HNI 

Iodide  of  tetra-ethyl-ammonium,.  (CgHg^gNjCg^sI  =  (^2^5)4^^ 

Similar  products  result  when  bromide  or  chloride  of  ethyl 
Is  substituted  for  the  iodide,  except  as  to  the  relative  proportions 
of  the  amines  obtained.  Thus  chloride  of  ethyl  produces  almost 
exclusively   EtHgNCl,  with    small    quantities  of    EtgHgNCl    and 


4  FORMATION  OF  AMINES. 

Et^NCl ;  ethyl  bromide  gives  chiefly  EtHgNBr,  with  very  appreciable 
quantities  of  EtgHgNBr  and  EtgHNBr,  but  very  little  Et^NBr ; 
while  ethyl  iodide  produces  EtHgNI,  EtgHgNI,  and  EtgHNI  in 
about  equal  proportions,  as  well  as  very  appreciable  quantities  of 
Et^NI  (Groves,  Jour.  Chem.  Soc,  xiii.  331). 

A  similar  series  of  products  is  obtained  by  heating  iodide, 
bromide,  or  nitrate  of  methyl  with  a  solution  of  ammonia  in 
methyl  alcohol.  When  the  methyl  nitrate  and  ammonia  solution 
are  used  in  equivalent  proportions  for  the  reaction — MeNOg^- 
H3N  =  MeH2N,HNOg,  monomethylamine  is  the  chief  product, 
though  more  or  less  of  each  of  the  more  highly  substituted  pro- 
ducts is  also  formed.  With  excess  of  methyl  nitrate,  the  nitrate 
of  tetramethyl-ammonium,  Me^N.NOg,  is  produced  in 
large  excess,  and  the  same  quaternary  compound  is  formed  if 
methyl  bromide  or  iodide  be  substituted  for  the  nitrate. 

The  complex  nature  of  the  products  obtained  by  treating  alkyl 
iodides,  &c.,  with  alcoholic  ammonia  is  due  to  the  tendency  of 
the  amines  first  produced  to  react  on  the  remaining  portions  of 
the  alkyl  iodide  or  other  salt  to  form  ammonium  iodide  and 
more  highly  substituted  amines.     Thus  ; — 

H3N  +  C,H,I  =  (CA)HsNI 
.  (C  A)H2N  +  C^H.I  =  (C2H,)H2NI 
(C^HJ^HN  +  C^H.I  =  (C2H,)3HNI 
(CA)3N  +  C,H,I  =  (CA)4NI 

The  hydriodides  of  the  amines  similarly  react  with  alkyl  iodides 
in  presence  of  ammonia  to  form  ammonium  iodide  and  more 
highly  substituted  amines. 

From  these  reactions  it  follows  that  the  hydriodide  of  diethyl- 
amine,  for  instance,  may  be  obtained  by  heating  the  bromide  or 
iodide  of  ethyl  with  a  calculated  amount  of  mono-ethylamine  in 
a  sealed  tube.  A  great  variety  of  mixed  amines  may  be  obtained 
by  precisely  similar  means. 

Distinction  and  Separation  of  Primary,  Secondary,  and 
Tertiary  Monamines. 

a.  If  an  amine  be  heated  to  100°,  under  pressure,  with  an  excess 
of  alkyl  iodide,  a  quaternary  iodide  will  at  length  be 
formed,  and  the  problem  whether  the  original  base  was  a  primary, 
secondary,  or  tertiary  amine  will  be  solved  by  comparing  the 
composition  of  the  ultimate  product  with  that  of  the  original 
base  or  its  hydriodide.  Thus,  if  methyl  iodide  has  been  the 
alkylising  agent  employed,  the  iodide  of  the  compound  ammonium 
ultimately  obtained  will  differ  from  the  hydriodide  of  the  original 


SEPARATION  OF  AMINES.  5 

base  by  SCHg,  if  the  amine  was  primary ;  by  2CH2,  if  secondary  ; 
and  by  CHg,  if  tertiary. 

h.  The  following  is  an  outline  of  the  method  devised  by 
A.  W.  Hofmann  for  the  separation  of  the  mixed  amines 
resulting  from  heating  ethyl  iodide  with  alcoholic  ammonia : — 
The  product  of  the  reaction  is  filtered  from  ammonium  iodide, 
which  is  nearly  insoluble  in  the  alcoholic  liquid,  and  is  evaporated 
to  dryness  to  get  rid  of  excess  of  alcohol,  free  ammonia,  and 
unchanged  alkyl  iodide.  The  residue  is  then  distilled  with  caustic 
potash,  when  the  hydriodides  of  the  amines  are  decomposed,  the 
bases  volatilising,  while  the  iodide  of  the  tetra-alkylated  ammonium 
base  remains  in  the  retort  unchanged  by,  and  insoluble  in,  the 
strong  potash  solution.  The  mixture  of  amines  is  conducted  over 
caustic  lime,  and  then  condensed  by  passage  through  a  well-cooled 
tube.  The  bases  are  then  treated  in  a  flask  with  one  and  half  times 
their  weight  of  ethyl  oxalate  (previously  dried  over  calcium 
chloride),  which  is  added  gradually  through  a  tapped  funnel.  This 
has  no  action  on  triethylamine  or  other  tertiary  bases,  but  converts 
diethylamine  into  liquid  ethyl  diethyl-oxamate,  and 
mono-ethylamine  into  solid  d  i  e  t  h  y  l-o  x  a  m  i  d  e,^  according  to 
the  following  equations  : — 

(0^)20^0,+  2(C2H,)NH,  =  C,0, 1  NH(§H  j  +  2(CA)0H 

Ethyl  oxalate.  Ethylamine.  Diethyl-oxamide.  Alcohol. 

2.  (C,H,),CA  +  (CA)2NH  =  C,0,{  Og^^«^^^+(CA)OH 

Ethyl  oxalate.  Diethylamine.       Ethyl  Diethyl-oxamate.  AlcohoL 

The  liquid  gets  very  hot,  but  for  the  completion  of  the  reaction 
the  mixture  should  be  heated  to  100°  for  several  days  in  a 
closed  vessel.  The  triethylamine,  which  has  taken  no  part  in 
the  reaction,  is  then  distilled  ofif  on  the  water-bath.  The  residue  is 
well  cooled,  and  the  solid  oxamide  separated  from  the  liquid  oxamate 
by    pressure.2     On    subsequent    distillation    with    caustic    potash, 

*  Diethyl  oxamide  may  also  be  separated  from  the  ethyl  diethyloxamate 
by  cold  water,  in  which  the  former  dissolves  easily,  the  latter  very  sparingly. 
If  hot  water  be  used,  the  separation  is  more  perfect  and  the  residual  oxamate 
quite  pure  ;  but  some  of  it  suffers  hydrolysis  and  goes  into  solution  as 
diethyloxamic  acid. 

'  Some  ethyl  monoethyloxamate,  C2O2  -j  ijg  c  H  ^^  always  formed  from 
the  primary  amines  in  this  reaction. 


1. 


6  SEPARATION  OF  AMINES. 

these  compounds  yield  the  primary  and  secondary  amines  respec- 
tively : — 

1.  C202(NH.C2H5)2+2H.(OK)=C20,(OK)2+2H(NH.C2H6) 

2.  C2O2  I  g^gA) +2H.(OK)  =  C202(OK)2+H.N(C2H,^^ 

The  foregoing  process  is  available,  with  certain  modifications  in 
detail,  for  the  separation  of  the  amines  of  methyl  and  other  homo- 
logues  of  ethyl,  and,  in  fact,  is  of  general  application  for  the  separa- 
tion of  primary,  secondary,  and  tertiary  amines;  the  first  class 
forming  oxamides,  the  second  oxamic  ethers,  and  the  third  being 
unacted  on  by  ethyl  oxamate. 

An  important  modification  in  the  foregoing  method  has  been 
made  by  I)  u  v  i  1 1  i  e  r  and  B  u  i  s  i  n  e  (Ann.  Ghim.  Phys.,  [5],  xxiii. 
289),  who  operate  on  an  aqueous  solution  of  the  bases.  Under 
these  conditions,  the  primary  amines  are  converted  by  ethyl  oxalate 
into  insoluble  or  sparingly  soluble  oxamides,  while  the  secondary 
and  tertiary  bases  are  unchanged,  or  at  any  rate  remain  wholly  in 
solution.  After  separating  the  oxamides  by  filtration,  the  mother- 
liquor^  [is  boiled  for  some  time,  which  causes  the  hydrolysis  of  the 
ethyl  diethyloxamate  with  formation  ofdiethyloxamic  acid, 
(C2H5)2N.C202.0H,  and  the  further  change  of  this  into  the  acid 
oxalate  of  diethylamine,  (C2H5)2HN.H2C204.^  This  salt 
separates  on  cooling,  and  yields  the  free  base  on  distillation  with 
alkali.  The  filtrate]  is  distilled  with  potash,  the  bases  dried  by 
caustic  potash,  and  dissolved  in  absolute  alcohol.  On  adding  ethyl 
oxalate  to  this  solution  the  secondary  amines  are  converted  into 
oxamic  ethers,  while  any  remaining  primary  amines  are  converted 
into  the  corresponding  oxamides.  After  allowing  the  mixture  to 
stand  for  twenty-four  hours  to  complete  the  reaction,  the  alcohol 
and  unchanged  tertiary  bases  are  distilled  off  on  the  water-bath 
The  oxamates  remaining  in  the  retort  may  be  converted  into  calcium 
salts  by  treatment  with  milk  of  lime,  or  the  secondary  bases  at 
once  liberated  and  recovered  by  distillation  with  caustic  potash.^ 

^  The  treatment  described  in  the  brackets  is  optional,  and  chiefly  of  advan- 
tage in  the  separation  of  ethylamines. 

^  The  conversion  into  calcium  salts  is  especially  suitable  for  the  treatment 
of  the  ethylamines.  The  precijatated  calcium  diethyloxamate  and  monoethyl- 
oxamate  are  filtered  ofl",  and  the  liltrate  treated  with  alcohol,  which  precipi- 
tates the  remainder  of  the  calcium  salts.  The  precipitates  are  treated  with 
boiling  water,  when  the  monoethyloxamate  dissolves,  and  is  deposited  again 
on  cooling  in  large  crystals,  which  on  distillation  with  potash  yield  ethylamine. 
On  concentrating  and  cooling  the  mother-liquors,  calcium  diethyloxamate 
separates.  It  is  recrystallised  from  alcohol,  washed  with  ether  to  remove  any 
adhering  oxamide,  and  distilled  with  potash,  when  it  yields  pure  diethylamine. 


REACTIOifS  OF  AMINES.  7 

Duvillier  and  Buisine  have  applied  this  method  to  the  analysis 
of  the  complex  mixture  of  amines  present  in  commercial  trimethyl- 
amine  from  vinasses  (page  13).  A.  MUller  {Bull.  Soc.  Chim.^ 
xlii.  202  ;  Jour.  CJiem.  Soc,  xlviii.  501)  has  described  a  method 
for  the  separation  of  amines  based  on  much  the  same  principle. 

The  primary,  secondary,  and  tertiary  monamines  may  also  be 
distinguished  by  the  following  reactions  : — 

c.  If  a  primary  monamine  be  boiledwithalcoholicpotash  and  chloro- 
form, the  characteristic  and  highly  disagreeable  odour  of  the  corre- 
sponding carbamine  or  isonitrile  is  evolved,  according  to  the 
reaction  :— MeNHg  +  CHCIg  +  3KH0  =  MeNC  +  SHgO  +  3KC1. 

d.  If  a  primary  fatty  monamine  be  dissolved  in  a  mixture  of 
equal  measures  of  alcohol  and  carbon  disulphide,  and  the  liquid 
then  boiled  down  to  one-half,  a  thiocarbamate  will  be  formed 
thus:— 2MeNH2+CS2  =  MeNH.CS.S.NMeH3. 

If  the  resultant  liquid  be  boiled  with  a  solution  of  mercuric  or 
ferric  chloride,  a  pungent  odour  of  mustard  oil  will  be  produced, 
owing  to  the  formation  of  an  alkyl  iso-thiocyanate  :^ — 

MeNH.CS.S.NMeHg  -f  HgClg  =  HgS  +  MeNCS  +  NMeHsCl. 

e.  Nitrous  acid  con^evts primary  fatty  monamines  into  the  corre- 
sponding alcohols  :— MeHgN  -f  NO.OH  =  Me.OH  -\-  OH2+ Ng. 

Aromatic  primary  amines  {e.g.,  aniline)  are  converted  by 
nitrous  acid  into  diazo-compound  s  : — PhNH2+N0.0H  = 
PLNiKOH  +  HgO. 

Secondary  amines,  whether  fatty  or  aromatic,  are  converted  by 
nitrous  acid  into  nitrosamines,  thus  : — Me2NH  +  NO.OH  = 
MegN.NO  +  HgO.  The  nitrosamines  are  yellow  liquids,  of  neutral 
character  and  aromatic  odour,  volatile  without  decomposition  in  a 
current  of  steam.  Weak  reducing  agents  convert  them  into 
hydrazines  (page  27)  j  but  by  more  powerful  hydrogenising 
agents,  or  by  warming  with  alcohol  and  hydrochloric  acid,  they  are 
reconverted  into  the  original  secondary  amines. 

Nitrous  acid  has  no  action  on  tertiary  fatty  amines.  It  converts 
most  tertiary  aromatic  amines  into  nitroso-derivatives 
which  still  possess  basic  properties. 

In  practice,  the  action  of  nitrous  acid  on  the  amines  is  best 
effected  by  distilling  their  hydrochlorides  with  a  strong  solution  of 
potassium  or  sodium  nitrite.  If  a  mixture  of  the  hydrochlorides 
of  the  three  methylamines  be  thus  treated,  the  monomethylamine 
is  destroyed  (with  formation  of  methyl  alcohol,  which  will  be  found 

*  In  the  case  of  aromatic  primaiy  amines,  the  product  is  usually  a  thio-urea, 
which  requires  to  be  treated  with  phosphoric  pentoxide  to  obtain  the  iso-thio 
cyanate. 


8  ASSAY  OF  MIXED  AMINES. 

in  the  distillate),  dimethylamim  is  converted  into  dimethyl- 
nitrosamine,  which  distils,^  while  the  hydrochloride  of  tri- 
methylamine  remains  in  the  retort  (mixed  with  excess  of  the 
metallic  nitrite),  and  on  distilling  it  with  caustic  alkali  the  free 
base  can  be  obtained. 

/.  Both  'primary  and  secondary  monamines  react  with  aldehydes 
to  form  indifiPerent  bodies.  The  reaction  between  oenanthol  and 
mono-  and  di-methylamine  respectively  is  as  follows : — 

H2.N.GH3  +  CeHi3.CH0  =  HgO  -f  C6H13.CH.NCH3 ;  and 

2HN(CH3)2 + CeH,3.CH0  =  H^O  -f  C6H,3.CH[N(CH3)2]2. 

This  reaction  has  been  utilised  by  Schiff  (Annalen,  clix.,  158) 
for  the  volumetric  assay  of  amines.  The  base  is  dissolved  in 
benzene,  fused  calcium  chloride  added,  and  then  a  standard  solution 
of  oenanthol  in  benzene  dropped  in  from  a  burette  as  long  as  water 
continues  to  separate.  Each  addition  of  the  oenanthol  solution 
produces  a  turbidity  from  separation  of  water,  but  this  is  absorbed 
by  the  calcium  chloride  on  gentle  agitation.  As  a  primary  amine 
reacts  with  twice  as  much  oenanthol  as  the  corresponding  secondary 
amine,  the  proportions  of  the  two  in  a  mixture  can  be  estimated  from 
the  result  of  the  titration,  provided  the  mean  combining  weight  of 
the  mixture  be  known,  or  ascertained  in  a  separate  experiment  by 
titration  with  standard  acid. 

g.  The  acidferrocyanides  of  the  tertiary  amines  are 
remarkably  insoluble  in  water.  They  are  precipitated  on  adding 
potassium  ferrocyanide  to  the  solutions  of  the  amines  acidulated  with 
hydrochloric  acid.  The  bases  can  be  recovered  from  their  ferro- 
cyanides  by  treating  the  precipitate  with  solution  of  cupric  sulphate, 
filtering,  and  removing  the  sulphuric  acid  and  excess  of  copper  from 
the  filtrate  by  baryta-water. 

Generic  Characters  of  Monamines. 

The  monamines,  as  a  class,  are  readily  volatile  liquids,  of  lower 
specific  gravity  than  water.  Their  boiling-points  rise  with  the 
number  of  carbon  atoms  in  the  molecule.  They  are  inflammable, 
burning  with  a  yellow  flame ;  and  the  lower  members  dissolve 
with  great  facility  in  water,  forming  strongly  alkaline  liquids 
of  an  ammoniacal  odour.  From  their  solutions,  ethylamine  and 
the  higher  homologues  can  be  separated  by  saturating  the  liquid 
with  caustic  potash.     By  boiling  the  aqueous  solutions  of  the  free 

*  On  separating  the  nitrosamine,  which  forms  a  yellow  oil,  from  the  aqueoui 
distillate,  treating  it  with  aqueous  hydrochloric  acid,  and  then  passing  hydro 
chloric  acid  gas  till  the  liquid  is  homogeneous,  the  hydrochloride  of  the 
secondary  amine  is  formed,  and  may  be  obtained  by  evaporation  of  the  solution. 


REACTIONS  OF  MONAMINES.  9 

bases,  or  of  their  salts  after  adding  excess  of  lime  or  fixed  caustic 
alkali,  the  monamines  can  be  completely  volatilised,  and  con- 
densed again  in  water  or  acid,  and  titrated  in  the  same  manner 
as  ammonia.  The  monamines  are  all  powerful  bases,  closely 
resembling  ammonia  in  their  general  characters.  They  form 
cry stalli sable  salts,  and  yield  chloroplatinates,  chlor- 
a  u  r  a  t  e  s,  and  alums,  exactly  similar  in  characters  and  consti- 
tution to  the  corresponding  compounds  of  ammonia.  The  mona- 
mines precipitate  magnesium  salts,  but  the  precipitated  mag- 
nesium hydroxide  dissolves  in  the  amine  hydrochloride,  forming 
a  double  salt  from  the  solution  of  which  phosphate  of  sodium 
precipitates  an  amino-magnesium  phosphate.  The  amines  thus 
behave  exactly  in  the  same  manner  as  ammonia. 

The  only  amines  (not  described  in  other  chapters)  requiring 
detailed  consideration  are  the  primary,  secondary,  and  tertiary 
monamines  of  methyl  and  ethyl.  These  bodies  are  typical  of 
the  amines  generally,  and  most  of  the  statements  made  respecting 
them  would  be  true  of  all  the  bodies  of  the  class.  Their 
aqueous  solutions  dissolve  silver  chloride,  and  behave  in  much 
the  same  manner  as  ammonia  with  metallic  salts ;  but  there  are 
some  interesting  differences,  as  shown  in  the  table  on  next  page, 
from  which  it  will  be  seen  that  certain  of  the  precipitates 
which  are  soluble  in  excess  of  ammonia  are  undissolved  by  the 
amines,  and  vice  versa} 

In  all  cases  a  solution  of  aluminium  phosphate  in  hydrochloric 
acid  behaves  similarly  to  a  solution  of  aluminium  chloride  (Taylor). 

Methylamine.     Monomethylamine. 

CH3) 

H  J 

Methylamine  exists  ready-formed  in  Mercuvialis  annua  and 
M.  perennis,  and,  as  obtained  (in  an  impure  state)  from  these 
plants,  was  formerly  known  as  mercurialine.  It  also  exists 
in  herring-brine,  coal-tar,  bone-oil,  and  the  products  of  the  distilla- 
tion of  wood,^  beetroot  molasses  (vinasses),  and  certain  alkaloids 

*  The  author  is  indebted  to  Leo  Taylor  for  repeating  and  enlarging 
on  the  experiments  of  Vincent,  on  whose  observations  the  table  is  chiefly 
founded.  Several  blanks  in  the  observations  of  Vincent  have  been  filled  by 
Taylor. 

^  The  presence  of  the  amines  of  methyl  in  pyroligneous  acid  and  wood  spirit 
is  probably  due  to  the  reaction  of  acetone  and  ammonia:  — CgHgO  +  NHs™ 
C2H40  +  (CH3).NH2.     This  equation  has  been  experimentally  verified. 


10 


REACTIONS  OF  AMINES  WITH  METALS. 


Metallic 
Salt. 

Ammonia. 

EthylamiTie. 

Methylamine. 

Dimethyl- 
amine. 

TrimethyU 
amine. 
{CH3)3N 

Aluminium. 

Insoluble 
(nearly). 

Soluble. 

Soluble. 

Soluble. 

Soluble. 

Cobalt. 

Blue  precipi- 
tate ;  sol- 
uble in  ex- 
cess to 
brown 
solution. 

Insoluble. 

Blue;  insol- 
uble in 
excess ; 
turned 
brownish 
on  heating. 

Blue;  insol- 
uble in 
excess ; 
turned 
brownish 
on  heating. 

Blue;  insol- 
uble in 
excess ; 
turned 
brownish 
on  heating. 

NickeL 

Soluble  in 
excess  to 
violet-blue 
solution. 

Insoluble. 

Apple-green ; 
insoluble 
in  excess. 

Apple-green ; 
insoluble 
in  excess. 

Apple-green ; 
insoluble 
in  excess. 

Zinc 

Very  soluble. 

Soluble. 

Soluble  in 
large  ex- 
cess ;  re- 
ppted on 
heating. 

Soluble  in 
large  ex- 
cess; re- 
ppted on 
heating. 

Soluble  in 
very  large 
excess ; 
reppted 
on  heating. 

Cadmium. 

Soluble. 

Insoluble. 

Insoluble. 

Insoluble. 

Insoluble. 

Silver. 

Brownish ; 
very  sol- 
uble in  ex- 
cess. 

Brownish ; 
soluble  in 
large  ex- 
cess ;  re 
ppted  on 
warming. 

Brownish ; 
soluble  in 
large  ex- 
cess; re- 
ppted on 
warming. 

Dirty  brown 
ppte 
changmg 
to  black ; 
sol.  large 
excess  to 
dark  solu- 
tion ;  re- 
ppted on 
warming. 

Cupric 

Blue ;  sol- 
uble in 
excess  to 
deep  blue 
solution. 

Soluble  with 
difficulty 
in  excess. 

Blue ;  soluble 
in  large 
excess  to 
deep  blue 
solution ; 
reppted 
dirty 
brown  on 
boiling. 

Blue ;  partly 
soluble  in 
large  ex- 
cess ;  re- 
ppted dirty 
brown  on 
boiling. 

Blue ;  partly 
soluble  in 
large  ex- 
cess ;  re- 
ppted dirty 
brown  on 
boiling. 

Mercuric. 

White. 

' 

White  ;  in- 
soluble. 

White;  sol- 
uble in 
much 
water. 

Yellow ; 
changing 
to  very 
pale  yel- 

Stannic. 

Insoluble. 

Very  soluble 
in  excess. 

... 

Soluble. 

Soluble. 

Antinionic. 

... 

... 

... 

Soluble. 

Soluble  in 
large  ex- 
cess. 

Gold. 

Insolubla 

Soluble. 

Brownish 
yellow  ppt; 
readily  sol- 
uble in 
excess  to 
orange-red 
liquid. 

Yellow  pre- 
cipitate ; 
soluble  in 
excess  to 
brown 
liquid. 

Ruthenium. 

Insoluble. 

Soluble 

... 

... 

.. 

Lead. 

Insoluble. 

... 

Insoluble. 

Insoluble. 

Insoluble. 

METHYLAMINE.  11 

(e.^.,  morphine,  codeine).  It  is  also  produced  when  caffeine  is 
boiled  with  baryta-water,  and  by  heating  hydrochloride  of  tri- 
methylamine  to  285°,  when  methyl  chloride  and  trimethylamine 
volatilise,  and  methylamine  hydrochloride  (mixed  with  some  ammo- 
nium chloride)  remains. 

Methylamine  may  be  prepared  by  the  action  of  alcoholic 
ammonia  on  methyl  iodide,  but  in  this  case  dimethylamine  and 
trimethylamine  are  also  produced  (page  3),  and  the  main  pro- 
duct is  iodide  of  tetramethyl-ammonium.  Methylamine  is  best 
obtained  pure  by  treating  one  equivalent  of  acetamide  with  two 
equivalents  of  bromine,  and  then  adding  a  10  per  cent,  solution  of 
caustic  potash  till  the  colour  of  the  bromine  has  nearly  dis- 
appeared : — 

C2H3O.NH2  -f  Brg  -f  2KH0  =  CgHsO.KBrK  -f  KBr  +  2H2O . 

Three  additional  equivalents  of  caustic  potash  are  now  dissolved 
to  a  10  per  cent,  solution,  and  heated  in  a  retort  to  70°  C.  The 
product  of  the  first  reaction  is  then  gradually  added  through  the 
tubulure.  The  gases  evolved  are  collected  in  hydrochloric  acid, 
and  on  evaporating  the  solution  a  mixture  of  the  hydrochlorides  of 
ammonia  and  methylamine  is  obtained,^  from  which  the  latter  only 
is  dissolved  by  absolute  alcohol.  On  distillation  with  caustic 
alkali  or  slaked  lime  the  salt  yields  the  base,  quite  free  from  di-  or 
tri-methylamine. 

Methylamine  boils  only  a  few  degrees  above  zero,  and  hence  is 
a  gas  at  ordinary  temperatures.  One  volume  of  water  at  12°'5  C. 
dissolves  1150  measures  of  the  gas,  and  hence  it  is  more  soluble 
even  than  ammonia,  which  methylamine  closely  resembles  in  odour 
and  general  characters,  but  is  distinguished  by  its  ready  inflam- 
mability— a  property  even  possessed  by  its  concentrated  aqueous 
solution.  It  burns  with  a  yellow  flame,  forming  carbon  dioxide 
water,  nitrogen,  and  hydrocyanic  acid. 

On  passing  a  succession  of  electric  sparks  through  methylamine, 
hydrocyanide  of  methylamine  is  produced,  and  this  is 
decomposed  by  a  continuation  of  the  treatment,  with  formation  of 
a  tarry  deposit.  When  passed  through  a  red-hot  tube,  methylamine 
is  decomposed  with  formation  of  hydrogen  and  ammonium 
cyanides,  methane,  and  hydrogen. 

The  behaviour  of  methylamine  with  metallic  solutions  (page  10; 
and  various  other  of  its  reactions  have  already  been  described. 
It  forms    a    series    of   readily    crystallisable    salts.     The    chloro- 

^  The  reaction  which  occurs  is  very  complex  (A.  "W.  H 0 f m an n,  Ber,,  xv. 
765),  but  the  main  decomposition  may  be  expressed  as  follows : — 
CH3.CO.NKBr  +  2HOK  =  CO(OK)2+KBr  +  CH3.NHj. 


12  DIMETHYLAMINE. 

plaiinate,  (KeH^'N)2PtC\Qy  is  insoluble  in  alcohol,  but  soluble 
in  boiling  water,  crystallising  on  cooling  in  beautiful  golden-yellow 
scales. 

A  method  for  the  proximate  analysis  of  the  bases  present  in 
crude  methylamine,  based  on  the  principles  of  the  process  described 
on  page  6,  has  been  described  by  A.  Mil  Her  {Bull.  Soc.  Ghim.y 
xlii.  202;  Journ.  Ghem.  Soc,  xlviii.  501). 


Dimethylamine. 

CH 
C2H7N  =  CH 


Dimethylamine  occurs  in  Peruvian  guano  and  pyroligneous  acid, 
and  is  also  present  in  the  products  of  the  distillation  of  vinasses. 

Dimethylamine  is  readily  separated  from  the  primary  and  tertiary 
methylamines  by  converting  it  into  ethyl  dimethyloxamate 
(pages  5,  6,  1 4),  or  into  dimethylnitrosamine  (page  7). 
On  distilling  the  first  of  these  derivatives  with  caustic  alkali, 
or  treating  the  second  with  fuming  hydrochloric  acid,  the  dimethyl- 
amine is  regenerated.  The  base  may  also  be  obtained  pure  by 
boiling  35  parts  of  nitroso-dimethylaniline  hydrochloride  with  a 
solution  of  15  parts  of  caustic  potash  in  400  of  water: — 

C6H4(NO).NMe2,HCl  +  KHO  =  KCl  +  C6H,(N0).0H  +  HNMeg. 

Dimethylamine  boils  at  8°-9°  C,  and  closely  resembles  the 
primary  and  tertiary  methylamines.  From  the  former  it  is  at  once 
distinguished  by  the  non-formation  of  a  precipitate  on  the  addition 
of  ethyl  oxalate  to  the  aqueous  solution  of  the  base  (page  6), 
and  the  non-production  of  an  isonitrile  on  treatment  with  alcoholic 
potash  and  chloroform.  From  trimethylamine  it  is  distinguished 
by  the  formation  of  a  nitrosamine  on  treating  it  with  nitrous 
acid,  or  one  of  its  salts  with  a  nitrite  (page  7). 

The  chloroplatinate,  (Me2H2N)2PtCl6,  crystallises  in  very  long 
needles. 

Trimethylamine. 

CH3) 

Trimethylamine,  often  improperly  called  propylamine,  a  base 
having  the  constitution  (CgH^)!!  N,  occurs  somewhat  frequently 
both  in  the  animal  and  vegetable  kingdom.  In  the  former  it  occurs 
notably  in  herring-brine,  and  has  been  detected  in  urine,  unputre- 


TRIMETHYLAMINE.  13 

fied  blood  of  the  calf,  cod-liver  oil,  and  other  animal  fluids.  In 
the  vegetable  kingdom,  trimethylamine  occurs  in  the  Chenopodium 
vulvaria  (stinking  goose-foot),  from  the  leaves  of  which  it  con- 
stantly exudes;  Arnica  montana;  Mercurialis  annua;  the  blossoms 
of  the  pear,  white- thorn  {Gratoegus  oxyacantha),  hawthorn,  and 
wild  cherry ;  and  in  ergot  ^  and  other  parasites  of  the  vegetable 
kingdom.  Trimethylamine  is  also  a  product  of  the  dry  distillation 
of  certain  alkaloids,  wood,  &c.,  but  especially  of  the  vinasses  or 
residue  left  after  the  distillation  of  the  spirit  from  fermented  beet- 
root molasses.  The  bases  obtained  by  the  destructive  distillation 
of  this  product  are  derived  from  the  b  e  t  a  i  n  e,  CgHj^NOg,  con- 
tained in  the  molasses,  and  consist  chiefly  of  the  monamines  of 
methyl,  among  which  trimethylamine  predominates.^ 

The  products  of  the  destructive  distillation  of  the  "  vinasses," 
left  after  the  distillation  of  the  fermented  beetroot-molasses,  vary 
^7ith  the  concentration  of  the  liquid.  As  the  proportion  of  water 
decreases,  the  quantity  of  ammonia  increases,  and  the  trimethyl- 
amine is  replaced  by  the  primary  and  secondary  methylamines. 
The  vinasses  from  different  localities  yield  varying  proportions  of 
gaseous  and  liquid  products  on  distillation,  the  nitriles  and  methylic 
alcohol  appearing  to  be  the  most  variable  constituents.* 

^  The  trimethylamine  of  ergot  is  probably  a  decomposition-product  of 
choline,  (CH3)3N(C2H40H).OH. 

2  Tlie  vinasses,  or  spent  wash  from  the  stills,  is  evaporated  till  it  acquires  a 
specific  gravity  of  1"31,  when  it  is  subjected  to  dry  distillation  in  cast-iron 
retorts.  The  aqueous  portion  of  the  distillate  contains  : — Ammonium  car- 
bonate, sulphydrate  and  cyanide;  methyl  alcohol,  methyl  sulphide,  and  methyl 
cyanide;  various  other  bodies  of  the  fatty  series;  and  a  large  proportion  of 
salts  of  trimethylamine.  The  tar  yields,  on  distillation  : — ammoniacal  liquor, 
various  oils,  pyridine  bases,  solid  hydrocarbons,  phenols,  and  pitch  of  superior 
quality.  The  aqueous  liquid  is  neutralised  with  sulphuric  acid  and  concen- 
trated, when  crystals  of  ammonium  sulphate  are  deposited,  and  vapours  of 
methyl  alcohol  are  evolved  together  with  methyl  cyanide  and  other  nitriles. 
The  methyl  cyanide  is  converted  in  ammonia  and  acetate  by  treatment  with 
an  alkali :— CH3.  NO  +  NaHO  +  H2O  -  H3N  +  CH3.  COONa.  The  dark-coloured 
mother-liquors  retain  the  trimethylamine  sulphate,  which  is  decomposed  by 
distillation  with  lime,  the  vapours  being  passed  into  hydrochloric  acid.  The  re- 
sultant solution  is  boiled  down  till  the  temperature  reaches  140°  C.  Ammonium 
chloride  crystallises  out  on  cooling,  and  the  mother-liquor  is  separated  and 
concentrated  till  the  boiling-point  rises  to  200°,  the  product  forming  com- 
mercial hydrochloride  of  trimethylamine,  from  which  the  free 
base  may  readily  be  obtained  by  treatment  with  lime  or  caustic  alkali. 

*  In  a  specimen  of  "commercial  trimethylamine,"  prepared  from  vinasses, 
Duvillier  and  Buisine  found  only  from  5  to  10  per  cent,  of  trimethyl- 
amine and  some  50  per  cent,  of  dimethylamine  ;  while  the  remainder  consisted 
of  raethylamine,  propylamine,  and  isobutylamine  in  about  equal  proportions ; 


14  AMINES  FROM  VIN ASSES. 

Trimethylamine  has  a  specific  gravity  of  0'673  at  0°,  and  boils 
between  9°  and  10°  C.  When  pure  and  concentrated,  trimethyl- 
the  ethylaniine  being  estimated  at  about  2  per  cent.,  and  ammonia  being  absent 
{Compt.  Bend.,  Ixxxix.  48).  The  method  employed  by  these  chemists  for  the 
separation  of  the  amines  in  question  was  as  follows  {Ami,  Chim.  Phys.,  [5], 
xxiii.  289) : — The  aqueous  solution  of  the  free  bases  was  treated  with  ethyl 
oxalate,  the  dense  white  precipitate  of  oxamides  filtered  off,  the  filtrate  con- 
centrated by  distillation,  and  the  further  precipitate  added  to  that  previously 
obtained.  By  treating  the  precipitate  with  hot  water  it  was  separated  into 
three  fractions.  The  most  insoluble  portion  (1)  consisted  of  dibutyl- 
oxamide  (or possibly  di-tsobutyloxamide),  which  melted  and  floated 
on  the  hot  water,  and  on  cooling  formed  a  solid  waxy  mass.  When  recrystal- 
lised  from  alcohol,  it  was  obtained  in  pearly  needles.  The  biUylamine, 
C4H9NH2,  obtained  by  distilling  the  oxamide  with  potash,  had  a  faintly 
aromatic  odour,  and  yielded  a  slightly  soluble  chloroplatinate,  crystallising  in 
orange-coloured  plates.  Of  the  oxamides  soluble  in  boiling  water,  thedipropyl 
compound  (2)  was  first  deposited.  It  crystallised  from  alcohol  in  pearly 
needles  melting  at  110°,  and  the  propylamine,  C3H7.NH2,  obtained  from  it 
gave  an  orange  chloroplatinate.  When  the  proportion  of  butylamine  and 
propylamine  was  small,  the  authors  preferred  to  utilise  the  comparative  insolu- 
bility of  their  sulphates  in  alcohol  to  separate  them  from  the  other  amines. 
The  most  soluble  portion  of  the  mixed  oxamides  (3)  was  deposited  in  opaque 
white  needles  or  grains,  and  consisted  of  dimethyloxamide.  The  base 
obtained  by  distilling  it  with  potash  was  converted  into  the  sulphate,  which 
on  treatment  with  boiling  absolute  alcohol  was  obtained  quite  pure,  and 
yielded  pure  methyl  amine  on  treatment  with  potash. 

The  mother-liquor  separated  from  the  oxamides  of  the  primary  amines  was 
distilled  with  caustic  potash,  and  the  dried  gas  collected  in  absolute  alcohol. 
A  portion  of  the  solution  was  then  titrated  with  standard  acid,  and  the 
remainder  gradually  added  to  a  quantity  of  ethyl  oxalate  sufficient  for  the 
reaction:— Me2NH  +  Et2C204  =  (MeHN)2C202  +  2EtOH;  assuming  the  alkalinity 
to  be  wholly  due  to  dimethylamine.  The  operation  was  conducted  in  a  flask, 
which  was  surrounded  with  ice  and  continually  shaken.  When  the  reaction  was 
completed,  the  flask  was  heated  on  the  water-bath,  and  the  alcohol  and  un- 
changed trimethylamine  distilled  off  and  collected  in  hydrochloric  acid.  It 
yielded  a  chloroplatinate  in  large  orange-red  crystals,  and  was  the  only  tertiary 
amine  found  in  the  mixture  of  bases  under  examination. 

The  syrupy  residue  left  in  the  flask  after  the  distillation  of  the  alcohol  and 
trimethylamine  consisted  of  the  ethyl  dialkylated-oxamates,  with  traces  of 
athyl  monalkylated-oxamates  and  oxamides  of  primary  amines.  It  was  treated 
with  water,  which  caused  hydrolysis  ;  and,  on  neutralising  the  liquid  with  milk 
of  lime,  calcium  ethyloxamate  and  propyloxamate  were  thrown  down,  which  on 
distillation  with  potash  yielded  ethylamine,  C2H5.NH2,  and  propylamine, 
J3H7.NH2.  On  treating  the  filtrate  from  the  calcium  oxamates  precipitate 
with  an  equal  volume  of  alcohol,  a  precipitate  was  formed  from  which  warm 
water  extracted  calcium  dimethyloxamate,  yielding  dimethylamine, 
(CH3)2lSrH,  on  distillation  with  potash,  while  the  less  soluble  portion  consisted 
of  calcium  monomethyloxamate,  yielding  methylamine  under  similar  treatment. 
lamine,  which  escaped  detection  on  Duvillier  and  Buisine'sfirst 


TRIMETHYLAMINE.  15 

amine  is  stated  to  have  a  purely  ammoniacal  odour;  but  when 
highly  diluted,  the  vapour  has  at  the  same  time  a  smell  of  ammonia 
and  a  peculiar  fishy  odour  suggestive  of  herring-brine.  The  latter 
odour  is  gradually  developed  by  adding  lime  to  a  solution  of  the  base, 
but  requires  some  time  to  reach  its  maximum  intensity  (L.  Taylor). 

Trimethylamine  is  apparently  soluble  in  all  proportions  of  cold 
water.  ^ 

A  mixture  of  equal  measures  of  trimethylamine  and  water  is 
inflammable. 

Trimethylamine  is  employed  for  preparing  pure  potassium  car- 
bonate from  the  chloride  by  a  method  analogous  to  the  ammonia- 
soda  process.  Ammonia  is  not  available,  because  of  the  nearly 
equal  solubility  in  water  of  amm  mium  chloride  and  acid  potassium 
carbonate,  whereas  the  hydrochloride  of  trimethylamine  is  much 
more  soluble. 

Trimethylamine  might,  primd  facie,  be  supposed  the  active  agent 
in  Wollheim's  process  of  treating  sewage  with  herring-brine 
and  lime  {Eng.  Patent  No.  15321,  1888);  but  those  who  have 
investigated  the  matter  incline  to  the  opinion  that  the  bactericide  is 
a  hitherto  unisolated  body  they  term  a  m  i  n  o  1,  produced  by  the 
action  of  lime  on  one  of  the  amines  of  herring-brine.  Pure 
trimethylamine  employed  without  lime  has  not  the  same  effect. 

Trimethylamine  is  distinguished  from  the  primary  and  secondary 
methylamines  by  its  negative  reaction  with  alcoholic  potash  and 
chloroform  (page  7),  ethyl  oxalate  (page  5),  and  nitrous  acid 
(page  7),  and  by  its  solution  in  excess  of  hydrochloric  acid  being 
precipitated  by  potassium  ferrocyanide  (page  8). 

Trimethylamine  has  been  employed  in  medicine,  and  is  said  to 
have  proved  of  value  in  the  treatment  of  gout  and  acute  rheumatism. 


examination  of  the  bases  from  viuasses,  owing  to  the  small  proportion  present, 
was  subsequently  detected  by  distilling  with  potash  the  mother-liquors  ob- 
tained by  treating  the  oxamides  with  water,  and  converting  the  bases  into 
sulphates.  On  treating  these  with  absolute  alcohol,  the  sulphate  of  methyl- 
amine  remained.  On  distilling  the  soluble  portion  with  alkali,  collecting  the 
bases  in  absolute  alcohol,  and  treating  the  solution  with  ethyl  oxalate,  as 
rdready  described,  the  ethylamine  was  converted  into  a  monoethyloxamate, 
from  which  the  calcium  salt  was  prepared  and  decomposed  by  alkali. 

^  According  to  Guthrie,  the  solubility  of  trimethylamine  in  water  is 
notably  diminished  by  heating,  the  liquid  becoming  distinctly  turbid  (com- 
pare nicotine)  from  partial  separation  of  the  base.  Thus  a  10  per  cent, 
solution  of  trimethylamine  in  water  became  turbid  at  22°  C. ;  an  8  per  cent,  at 
24°*5  ;  and  a  4  per  cent,  solution  at  about  42°  C.  Leo  Taylor  has  failed 
to  confirm  Guthrie's  observations,  which  were  not  improbably  made  on  impure 
material. 


16  TRIMETHYLAMINE  HYDROCHLOKIDE. 

(A  valuable  description  of  its  therapeutic  effects  will  be  found  in 
the  Year -Bonk  of  Pharmacy  for  1873,  pages  1 9  7-2  6  2.)  i 

Trimethylamine  combines  with  carbon  disulphide  at  the  ordinary 
temperature  with  great  evolution  of  heat,  according  to  the  equation 
CS2  +  (CH3)3N  =  N(CH3)2.CS.S.CH3.  The  product,  which  may  be 
regarded  as  trimethyl-thiocarbamic  acid,  is  prepared 
more  readily  by  passing  gaseous  trimethylamine  into  a  mixture  of 
carbon  disulphide  and  alcohol.  It  is  obtained  on  evaporating  the 
solvent  in  white  rhombic  needles,  melts  at  125°,  and  decomposes 
gradually  at  the  ordinary  temperature.  It  is  soluble  in  dilute 
alcohol  and  water,  but  nearly  insoluble  in  absolute  alcohol,  ether, 
chloroform,  or  benzene.  Dilute  acid  combine  with  it  to  form  salts, 
but  strong  acids  and  alkalies  decompose  it  into  carbon  disulphide 
and  trimethylamine. 

Trimethylamine  Hydrochloride.  Hydrochlorate  of  trimethyl- 
amine. Chloride  of  Trimethylammonium.  (CH3)3HNC1.  This  salt 
is  obtained  by  neutralising  trimethylamine  with  hydrochloric  acid. 
It  differs  from  ammonium  chloride  in  being  extremely  deliquescent, 
and  soluble  in  absolute  alcohol.  The  fishy  odour  of  the  base 
liberated  on  treating  the  salt  with  lime  or  caustic  alkali  further 
distinguishes  it  from  ammonium  chloride.  With  platinic  chloride 
it  unites  to  form  the  chlornplatinate,  (MegHXj^PtClg,  a  com- 
pound which  crystallises  in  orange  octohedra,  sparingly  soluble 
in  absolute  alcohol. 

When  heated  to  260°-285°  C,  trimethylamine  hydrochloride 
is  decomposed  with  formation  of  free  trimethylamine, 
ammonia,  and  methyl    chloride: — 

SMeHNCl  =  2Me3N  +  H3N  +  3MeCl. 

This  reaction  has  been  utilised  by  Camille  Vincent  for  the  manu- 
facture of  methyl  chloride.  The  vapours  are  passed  through  hydro- 
chloric acid,  which  absorbs  the  bases,  while  the  gaseous  methyl 
chloride  passes  on.  It  is  washed  by  dilute  caustic  soda  and  dried 
by  strong  sulphuric  acid,  after  which  it  is  collected  in  a  gas-holder, 
from  whence  it  is  pumped  into  strong  wrought-iron  cylinders,  in 
which  it  is  condensed  to  liquid.  The  vapour  of  liquid  methyl 
chloride  has  a  tension  of  2*5  atmospheres  at  0°  and  4'8  at  20°  C. 

1  The  solution  of  trimethylamine  for  medicinal  use  should  be  clear,  colour- 
less, and  of  1'124  specific  gravity.  It  should  have  a  peculiar  odour,  recalling 
that  of  ammonia  and  herring-brine,  be  miscible  in  all  proportions  with  water 
and  alcohol,  and  contain  20  per  cent,  of  the  base.  One  measure  of  hydro- 
chloric acid,  of  1'170  specific  gravity,  should  neutralise  three  measures  of  the 
solution  of  the  base,  and  the  salt  obtained  on  evaporating  the  resultant  solu- 
tion should  be  completely  soluble  in  absolute  alcohol. 


ETHYLAMINES. 


17 


Methyl  chloride  is  extensively  used  in  the  aniline-dye  manufacture 
for  preparing  methylaniline  and  dimethylaniline,  which  compounds 
form  the  starting-points  of  numerous  colouring  matters. 

Ethylamines. 

The  amines  of  ethyl  are  obtainable  in  the  manner  already 
described  (page  3).  A  convenient  source  of  the  primary  amine, 
C2H5.NH2,  is  the  crude  ethyl  chloride  obtained  as  a  bye-product  in 
the  manufacture  of  chloral  (A.  W.  H  0  f  m  a  n  n,  Ber.,  iii.  109,  776). 
When  ethyl  chloride  is  heated  to  90°  under  pressure  with  an 
equivalent  proportion  of  strong  aqueous  ammonia,  a  layer  of  triethyl- 
amine  containing  ammonia  is  formed,  while  the  aqueous  liquid 
contains  the  hydrochlorides  of  ethylamine  and  diethylaraine. 
When  a  similar  mixture  of  aqueous  ammonia  and  ethyl  chloride 
is  heated  under  pressure  to  150°  C,  H^NCl,  EtHgNCl,  and  Et^NCl 
are  the  chief  "products,  only  traces  of  EtgHgNCl  and  EtgHNCl 
being  formed. 

The  amines  of  ethyl  can  be  separated  by  methods  already 
described.  They  present  the  closest  analogy  to  the  corresponding 
methyl  bases.  Various  differences  between  the  three  amines  are 
described  on  page  4  et  seq.  The  following  table  shows  other  of 
their  characteristic  properties. 


Ethylamine. 

DIETHYLAMINE. 

Triethylamine. 

Formula. 

(C2H5)H2N 

(C2H5)oHN 

(C2H5)3N 

BoiUng-point,  °  C. 

19 

56 

90 

Specific  gravity. 

|0-6964 

-0-7062 

X 

?2o-7277 

X 

|o-708 

fo-706 

Reaction  with   zinc 
sulpliate. 

Precipitate  soluble  in 
excess. 

Precipitate  insoluble 
in  excess. 

Precipitate        in- 
soluble in  excess. 

Product  when  boiled 
with  nitrous  acid 
(or  a  salt  of   the 
bases  with  sodium 
nitrite  solution). 

Alcohol  and   nitro- 
gen. 

Diethylnitrosamine ; 
a     neutral      oily 
liquid   boiUng   at 
177%  and  distilling 
with  steam  (page 
7). 

Unchanged. 

Hydrochloride. 

Deliquescent  laminse 
and  prisms. 

Non-deliquescent 
plates. 

Non-deliquescent 
laminae. 

Platinichloride. 

Hexagonal       rhom- 
bohedra ;     mode- 
rately soluble   in 
water. 

Monoclinic ;    mode- 
rately soluble. 

Monoclinic;    very 
soluble. 

Acid  ferrocyanide. 

i 

Soluble. 

Soluble. 

Very       sparingly 
soluble. 

VOL.  III.  PART  II. 


18  TETRA- ALKYLATED  AMMONIUMS. 

AMMONIUM   BASES. 

By  the  action  of  excess  of  an  alkyl  iodide  on  ammonia  or  an 
amine,  all  the  hydrogen  atoms  of  ammonia  can  be  replaced  by 
alkyl  radicals,  the  tertiary  amines  thus  formed  combining  with 
another  molecule  of  alkyl  iodide  to  produce  the  iodide  of  a 
tetra-alkylated  ammonium.  When  methyl  iodide  has 
acted  on  ammonia,  the  product  is  tetramethyl-ammonium  iodide, 
(CHg)^]!^!;  but  by  obvious  modifications  in  the  process,  similar 
compounds  containing  other  alkyl-radicals  can  be  obtained. 
Thus,  H  0  f  m  a  n  n  prepared  the  iodide  of  methyl-ethyl- 
amyl-phenyl-ammoni  u  m:— (CH3)(C2H5)(C5Hii)(C6H5)NI. 
The  same  product  results  from  the  action  of  ethyl  iodide  on 
trimethylamine  as  by  the  action  of  methyl  iodide  on  dimethyl- 
ethylamine.  This  fact  proves  that  the  body  formed  is  not  merely 
a  molecular  compound  of  the  constitution 
CH3)  CH3) 

CHgU-.C^H,!;  or     CH3  U.CH3I ; 
CH3  j  C2H5  ) 

but  that  it  is  the  true  iodide  of  a  tetra-alkylated  ammonium  : — 

CH3 

The  identity  of  these  and  similar  compounds  furnishes  important 
evidence  of  the  pentavalent  character  of  nitrogen. 

The  iodides  of  the  tetra-alkylated  ammoniums  are  quite  un- 
acted on  by  caustic  potash  even  on  heating,  but  react  with  recently 
precipitated  argentic  oxide  to  form  iodide  of  silver  and  the 
hydroxides  of  the  tetra-alkylated  ammoniums. 
These  hydroxides  are  non-volatile,  syrupy  or  solid  deliquescent 
substances,  of  highly  caustic,  alkaline  character,  presenting,  as 
a  class,  a  strong  analogy  to  caustic  potash.  Many  of  them  have 
marked  poisonous  characters. 

Such  of  the  natural  vegetable  alkaloids  as  have  the  constitution 
of  tertiary  bases  unite  with  alkyl  iodides  to  form  compounds 
which  have  the  characters  of  iodides  of  compound  ammoniums, 
from  which  the  corresponding  hydroxides  can  be  prepared,  as 
above  described,  by  reaction  with  oxide  of  silver.  Thus,  for 
example,  from  morphine,  Ci^HigNOg,  may  be  prepared : — 

Ethylmorphium  iodide, ....     CjyHjgOg  \^j 
Ethylmorphium  hydroxide,      .     .     C17H19O3  ]  ^  ^.-rr 


COMPOUND   AMMONIUM   BASES.  19 

These  bodies  are  sometimes  formulated  and  described  as  the 
hydriodide  and  hydrate  of  ethylmorphine,  Ci7Hi8(C2H5)N03 ;  but 
such  a  view  is  inconsistent  with  their  characters. 

Similar  bodies  are  obtained  by  action  of  alkyl  iodides  on 
strychnine.  The  hydroxides  of  methyl-  and  ethyl-strychnium 
(C2iH.^2MeN02.0H  and  C2iH22EtN02.0H)  are  strong,  very  soluble 
bases,  which  form  carbonates  and  precipitate  metallic  hydroxides 
from  metallic  solutions.  In  their  physiological  action  they  simulate 
the  paralysing  action  of  curarine  rather  than  the  tetanic  poisoning 
of  strychnine  itself. 

Similar  bases  can  be  obtained  by  the  action  of  alkyl  salts  on 
diamines  or  ammonia.  Thus,  an  end-product  of  the  action  of 
excess  of  ethylene  dibromide  on  ammonia  is  tetra-ethylene- 
di-ammonium-dibromide  (C2H4)4N2Br2,  from  which  the 
hydroxide,  (C2H4)4N2.0H,  can  be  obtained  by  treatment  with 
oxide  of  silver.  This  base  is  a  powerful  caustic  alkali  and  non- 
volatile. 

Choline  and  neurine,  described  in  the  chapter  on  "Animal 
Base  s,"  are  natural  products  having  the  constitution  of  am- 
monium bases.     Thus : — 

Choline.  Trimethyl-hydroxyethyl-  )   .    .  (CH3)3         1  -j^  ^^t 
ammonium  hydroxide,  j   .    .  (C2H4.OH)  J 

Neurine.  Trimethyl-vinyl-ammonium  "j  .    .     (CH3)3  )  ^  ^^ 
hydroxide,  J.    .     (C2H3)|^^-^^ 

It  will  be  observed  that  neurine  and  choline  only  differ  from 
each  other  by  the  elements  of  water. 

Bases  of  similar  characters  and  constitution  have  been  prepared, 
containing  phosphorus,  arsenic,  or  antimony  in  place  of  nitrogen. 
Thus,  there  have  been  obtained  : — 

Tetramethyl-ammonium  hydroxide,     .  .  Me^N.OH 

Trimethyl-ethyl-phosphonium  hydroxide,  .  MegEtP.OH 

Tetrethyl-arsonium  hydroxide,  .  .  Et^As.GH 

Tetrethyl-stibonium  hydroxide,  ,  .  Et^Sb.OH 

Tetrethyl-ammonium  Compounds. 

When  perfectly  anhydrous  ethyl  iodide  is  added  to  trimethyl- 
amine  previously  dried  over  caustic  potash,  combination  gradually 
occurs  with  evolution  of  heat,  and  in  a  few  days  the  mixture  sets 
to  a  solid  mass  of 

Tetrethylammonium  Iodide^  (C2H5)^NI.  This  compound  is  pre- 
ferably prepared  by  exposing  a  mixture  of  equivalent  proportions 
of  triethylamine  and  ethyl  iodide  to  a  temperature  of  100°  for  a 


20  TETRETHYLAMMONIUM   COMPOUNDS. 

few  minutes  in  a  flask  furnished  with  a  well-cooled  inverted  con- 
denser, or  preferably  in  a  sealed  tube.  Violent  reaction  ensues, 
and,  on  cooling,  the  product  sets  to  a  hard  mass  of  crystals.  On 
dissolving  the  mass  in  water,  and  allowing  the  solution  to  evapo- 
rate spontaneously,  the  iodide  is  obtained  in  extremely  bitter  crys- 
tals of  considerable  size,  which,  when  pure,  are  colourless,  but  are 
apt    to    be    mixed    with    reddish    crystals    of    the    tri-iodide, 

(CA)4NI,l2.' 

Tetrethylammonium  iodide  is  not  volatile  at  100°  C,  but  when 
rapidly  heated  in  a  retort  to  a  higher  temperature  it  melts  and 
sufi'ers  decomposition  into  ethyl  iodide  and  tri  m  ethyl- 
am  i  n  e,  which  form  separate  layers  in  the  receiver  but  re-unite  to 
produce  the  original  compound. 

Tetrethylammonium  iodide  is  wholly  undecomposed  by  treat- 
ment with  caustic  potash  or  soda,  but  is  much  less  soluble  in 
caustic  alkaline  solutions  than  in  water.  Hence,  on  adding  excess 
of  caustic  potash  to  its  concentrated  aqueous  solution,  a  solid  crys- 
talline mass  is  produced.  This  behaviour  sharply  distinguishes 
the  iodide  of  tetrethyl-ammonium  (and  of  other  compound  ammo- 
niums) from  the  compounds  EtgHNI,  EtgHNI,  and  EtH^NI,  which 
are  at  once  decomposed  by  caustic  alkali,  with  liberation  of  the 
corresponding  amine.  The  aqueous  solution  of  tetrethylammonium 
iodide  reacts  with  argentic  nitrate  or  sulphate  to  form  a  precipitate 
of  argentic  iodide  and  a  solution  of  the  tetrethylammonium  nitrate 
or  sulphate. 

Tetrethylammonium  Hydroxide,  (C2H5)4N.0H,  is  obtained  in 
solution  by  adding  freshly-precipitated  oxide  of  silver  to  a  dilute 
and  warm  solution  of  tetrethylammonium  iodide,  until  the  brown 
colour  of  the  silver  oxide  ceases  to  change  into  the  lemon-yellow 
of  the  iodide.  The  solution  is  then  filtered,  and  may  be  evaporated 
to  a  considerable  extent  at  a  gentle  heat,  but  further  concentration 
must  be  conducted  in  vacuo,  at  the  ordinary  temperature,  over  sul- 
phuric acid  and  lime.  Long,  hair-like,  deliquescent  needles  of 
the  base  are  deposited,  but  these  subsequently  disappear,  and  the 
liquid  ultimately  dries  up  to  a  semi-solid  mass. 

Tetrethylammonium  hydroxide  presents  the  closest  analogy  to 
caustic  potash.  It  is  highly  deliquescent,  absorbs  carbon  dioxide 
from  the  air,  and  the  aqueous  solution  has  a  strong  alkaline  re- 
action. It  has  an  alkaline,  caustic,  and  extremely  bitter  taste,  and 
in  a  concentrated  state  burns  the  tongue  and  acts  on  the  skin 
like  caustic  potash.  With  metallic  solutions  it  behaves  like  the 
caustic  alkalies,  except  that  aluminium  hydroxide  is  soluble  with 

1  This  compound  is  readily  obtained  by  dissolving  iodine  in  a  solution  of 
tetrethylammonium  iodide. 


TETRETHYL AMMONIUM  COMPOUNDS.  21 

difficulty  in  excess  of  the   reagent,  and  chromic  hydroxide  is  quite 
insoluble. 

A  moderately  strong  solution  of  tetrethylammonium  hydroxide 
may  be  boiled  without  decomposition ;  but  in  a  concentrated  state, 
even  at  100°,  the  liquid  froths  strongly,  and  the  base  is  resolved 
gradually  but  completely  into  triethylamine,  ethylene, 
and  water  :— (C2H5)N.OH  =  (C2H6)3N  +  CgH^  +  H.OH.i  This 
reaction  affords  a  convenient  means  of  obtaining  triethylamine 
unmixed  with  the  primary  and  secondary  amines. 

When  a  solution  of  tetrethylammonium  hydroxide  is  boiled  with 
a  slight  excess  of  ethyl  iodide  for  twenty-four  hours,  under  a  reflux 
condenser,  the  solution  becomes  perfectly  neutral,  the  following  reac- 
tion occurring  :_(C2H5)4N.OH  +  C^R.l  =  (CgH^^NI -f  CgH^.OH. 

Tetrethylammonium  hydroxide  also  hydrolyses  ethyl  oxalate 
and  saponifies  fats  as  readily  as  caustic  potash. 

On  adding  caustic  potash  and  potassium  iodide  to  a  strong  solu- 
tion of  tetrethylammonium  hydroxide,  a  white  crystalline  mass  of 
tetrethylammonium  iodide  is  produced. 

The  salts  of  tetrethylammonium  are  mostly  crystallisable  and 
readily  soluble. 

Tetrethylammonium  Chl&nde,  (C2Hg)4NCl,  obtained  by  neutralis- 
ing the  hydroxide  with  hydrochloric  acid,  is  crystalline  and  highly 
deliquescent.  It  forms  double  salts  with  auric,  mercuric,  and  platinic 
chlorides.  Tetrethylammonium  chloroplatinate,  (Et4N)2PtClQ,  is 
thrown  down  immediately  as  an  orange-yellow  precipitate,  con- 
sisting of  microscopic  octahedra,  on  adding  platinic  chloride  to  a 
solution  of  tetrethylammonium  chloride.  It  is  slightly  soluble  in 
water,  and  less  soluble  in  alcohol  and  ether. 

^  Collie  and  Schryver  {Jour.  Chem.  Soc,  Ivii.  767)  have  recently 
shown  that  when  a  mixed  quaternary-ammonium  chloride  or  hydroxide  (made 
from  trimethylamiue  or  triethylamine)  is  heated,  amixedtertiaryamine 
is  always  produced  in  greater  or  less  amount.  With  triphenylmethylammo- 
nium  the  only  product  is  dimetliylplienylamine,  while  with  the  allyl-  and 
isopropyl-trimethylammonium  compounds,  the  chief  tertiary  amine  formed  by 
the  action  of  heat  is  trimethylamiue  In  the  case  of  the  chlorides,  the 
methyl-group  is  very  easily  eliminated  as  methyl  chloride;  whilst  in 
the  case  of  the  hydroxides,  the  ethyl-group  almost  invariably  splits  away  as 
ethylene.  (See  a  later  paper  by  S e li  r y  v e r  on  the  asymmetry  of  nitrogen 
in  substituted  ammonium  compounds.     Froc.  Chem,  Soc.,  1891,  page  39.) 


HYDRAZINES. 


The  name  hydrazine  M'as  first  applied  by  E.  Fischer 
to  a  hypothetical  base,  having  the  constitution  of  diamidogen, 
HgN.NHg.  Since  then  the  base  itself  has  been  obtained  in  the 
form  of  a  hydrate,  and  possibly  also  in  the  free  state. 

Hydrazine.     Diamidogen.     Diamide.     IS'gH^  or  H2N.NH2. 

Hydrazine  is  obtained  by  the  decomposition  of  triazo-acetic 
acid  by  heating  it  with  water  or  mineral  acids,  when  the  following 
reaction  occurs  : — 

C3H3Ng(COOH)3  +  6H2O  =  3N2H4  +  SC^H^O^. 

Triazo-acetic  acid.  Water.        Hydrazine.   Oxalic  acid. 

The  oxalic  acid  is  more  or  less  split  up,  according  to  the 
temperature  and  the  strength  of  the  acid  employed,  into  carbonic 
and  formic  acids,  so  that  when  only  water  is  used  the  hydrazine 
separates  as  a  formate;  but  if  a  mineral  acid  be  present  it 
forms  the  corresponding  salt. 

Hydrazine  has  an  extraordinary  affinity  for  water,  readily 
forming  a  hydrate,  ^2^i>^2^>  which  it  does  also  when  set 
free  from  its  salts  by  caustic  alkalies  or  lime.^  This  hydrate 
is  a  liquid  fuming  in  the  air  and  boiling  unaltered  at  119°  C, 
and  can  be  easily  separated  from  water  by  distillation,  though 
some  of  it  passes  over  with  the  steam.  When  heated  with  barium 
oxide  in  a  sealed  tube  to  170°,  some  anhydrous  hydrazine  appears 
to  be  formed  and  escapes  as  a  white  fume  on  opening  the  tube. 

The  solution  of  hydrazine  turns  reddened  litmus-paper  a  deep 
blue,  and  gives  white  fumes  with  acid  vapours.  In  a  concentrated 
state  it  has  a  very  peculiar  odour,  only  slightly  resembling  that  of 

•^Hydrazine  hydrate  is  best  prepared  (Cur tins  and  Schultz)  by  dis- 
tilling a  mixture  of  eleven  parts  of  hydrazine  sulphate  with  four  of  caustic 
potash  and  one  of  water  in  a  silver  retort  provided  with  a  silver  condenser. 
When  the  last  drop  has  passed  over,  the  distillate  is  fractionated.  After  four 
fractionations  the  last  portions  boil  constantly  at  119°.  Curtius  and  Jay 
{Jour.  Pract.  Chem.,  [2],  xxxix.  27)  prepare  hydrazine  hydrate  by  heating  the 
hydrochloride  of  the  base  with  caustic  lime  in  a  silver  retort,  and  passing  the 
vapours  through  a  heated  silver  tube  containing  caustic  lime. 


SALTS  OF   HYDRAZINE.  23 

ammonia.  It  powerfully  affects  the  nose  and  throat,  has  an 
alkaline  taste,  and  leaves  a  burning  sensation  on  the  tongue. 
When  boiling,  the  solution  attacks  glass,  and  quickly  destroys  corks 
and  india-rubber.  Hydrazine,  like  hydroxylamine,  is  a  strong 
poison  of  universal  character. 

Hydrazine  reduces  Fehling's  solution  and  ammonio-nitrate  of 
silver  in  the  cold.  With  cupric  sulphate  it  yields  a  red  precipitate 
(?  cuprous  oxide),  with  mercuric  chloride  a  white  precipitate,  and 
precipitates  alumina  from  a  solution  of  alum.  With  aromatic  alde- 
hydes and  ketones  it  yields  sparingly  soluble  crystalline  compounds. 

Salts  of  Hydrazine. 

Hydrazine  combines  with  one  or  two  molecules  of  monobasic 
acids  to  form  very  stable  salts,  which  are  usually  crystalline  and 
isomorphous  with  the  corresponding  ammonium  salts.  The  salts 
Hz,2HR  crystallise  in  the  regular  system  and  are  readily  soluble 
in  water,  but  nearly  insoluble  in  alcohol.  The  mono-acid  salts, 
HzHR,  are  easily  soluble  in  water  and  warm  alcohol,  from  which 
they  crystallise  well.  The  salts  of  both  classes  are  insoluble  in 
ether,  benzene,  &c.  In  acid  solution,  the  salts  of  hydrazine  possess 
remarkably  strong  reducing  properties,  and  are  powerfully  toxic 
towards  the  lower  organisms.  Peptone  solutions  containing  0*1 
per  cent,  of  hydrazine  sulphate  are  unable  to  support  bacterial  life. 

Hydrazine  Diliydrochloride,  '^^^,^HC\,  crystallises  from  hot 
water  in  large  glassy  octahedra  that  are  freely  soluble  in  water, 
but  less  so  in  alcohol.  On  treatment  with  platinic  chloride 
it  does  not  yield  a  chloroplatinate,  but  is  decomposed  with 
evolution  of  much  nitrogen.  It  melts  at  198°  C,  with  evolution  of 
hydrochloric  acid,  to  a  clear  glass  consisting  of  the  monohydro- 
chloride,  KgH^jHCl,  and  this  on  further  heating  to  240°  C.  is 
decomposed  into  ammonium  chloride,  nitrogen,  and  hydrogen. 

Hydrazine  Sulphate,  l^^^^^^^i^  according  to  T.  Curtius, 
is  best  obtained  from  ethyl  diazo-acetate,  which  on  treatment 
with  hot  concentrated  caustic  potash  yields  the  ])otassium  salt 
of  an  acid  which  separates  in  golden  yellow  tablets  on  addition 
of  a  mineral  acid.  On  digesting  the  yellow  aqueous  solution 
of  these  with  very  dilute  sulphuric  acid,  the  colour  disappears 
without  evolution  of  gas,  and  on  cooling  crystals  of  the  sparingly 
soluble  hydrazine  sulphate  are  obtained.  From  the  sulphate, 
other  salts  of  hydrazine  may  be  prepared  by  double  decomposition 
with  barium  salts. 

Salts  of  hydrazine  in  solution  are  decomposed  by  sodium  nitrite, 
with  evolution  of  gas  attended  by  much  frothing.  The  reaction 
is  analogous  to  the  decomposition  of  ammonia  salts  by  a  nitrite,  with 
the    difference    that    whereas    in   the    latter    case  (a)  nitrogen    is 


24  AZOIMIDE.      IMIDAZOXC  ACID. 

formed,  in  the  case  of  hydrazine  (6)  a  z  o  i  m  i  d  e,  HNg,  is  found 
among  the  products  of  the  reaction  : — 

(a)  :NH3,HC1  +NaN02  =  :N^aCl  +  2H20  +  N2. 

(b)  NgH^^Cl  +  KaNOg  =  NaCl  +  2H,0  +  H^^3. 

AzoiMiDE.     Imidazoic  Acid.     HNo  =  HN<:'.. 

The  above  reaction  is  not  a  suitable  one  for  the  preparation 
of  this  remarkable  body,  which,  according  to  its  discoverer,  T. 
Curtius  (Ber.,  xxiii.  3023),  is  best  obtained  by  decomposing 
nitroso-hippurylhydrazine,  NHBz.CH2.CO.N(:N^O).NH2, 
with  dilute  soda,  which  splits  it  up  into  hippuric  acid  and  the 
sodium  salt  of  azoimide  : — 

NHBz.CH2.CO.N(i^O).NH2  +  2KaH0  =  NHBz.CH2.C00Na  + 
2H20  +  NaN3. 

On  distilling  the  compound  NaNg  with  dilute  sulphuric  acid, 
imidazoic  acid  volatilises  with  the  steam,  which  when  passed  into  a 
neutral  solution  of  nitrate  of  silver  gives  a  precipitate  of  the 
silver  salt.  This  is  washed  and  decomposed  by  dilute  sulphuric 
acid,  the  solution  being  used  instead  of  silver  nitrate  to  absorb 
the  vapours  of  imidazoic  acid.  By  repeating  this  process,  a 
solution  containing  27  per  cent,  of  the  new  acid  is  obtainable. 

In  the  anhydrous  state,  imidazoic  acid  is  a  colourless  gas 
of  a  peculiarly  nauseous  odour,  and  condensible  on  cooling  to  an 
extremely  explosive  liquid.  It  is  very  soluble  in  water,  and 
on  distillation  of  the  liquid  a  concentrated  acid  passes  over, 
the  distillate  gradually  becoming  weaker  until  an  acid  of 
constant  composition  and  boiling-point  distils.  The  solution 
reddens  litmus,  and  gives  white  fumes  with  ammonia,  of  the  salt 
NH3.HN3  or  N4H4,  which  sublimes  completely  at  100°  0.,  but 
does  not  crystallise  in  the  cubic  system  like  ammonium  chloride. 
Iron,  zinc,  copper,  aluminium  and  magnesium  dissolve  readily  in 
dilute  imidazoic  acid  (7  per  cent.)  with  evolution  of  hydrogen, 
and  gold  is  dissolved  with  formation  of  a  red  salt.  The  silver 
(AgNg)  and  mercurous  salts  of  imidazoic  acid  are  insoluble, 
the  former  closely  resembling  silver  chloride,  but  not  blackening 
in  the  light.  Both  the  silver  and  the  mercurous  salts  are 
extraordinarily  explosive,  0*001  gramme  of  the  former  indenting 
an  iron  plate  on  which  it  is  heated  to  250°.  Barium  iinidazoate, 
BaNg,  separates  from  concentrated  solutions  in  short  shining 
anhydrous  crystals,  which  explode  with  a  green  flash  when 
heated,  or  exposed  to  a  strong  green  light.  The  solution  of  cupric 
imidazoate  deposits  cuprous  oxide  on  boiling.     The  free  acid  is 


SUBSTITUTED   HYDRAZINES.  25 

liberated  from  any  of  the  imidoazoates  on  treatment  with  dilute 
sulphuric  acid.  With  concentrated  sulphuric  acid,  the  azoimide 
is  itself  decomposed.  Etlters  of  imidazole  acid  have  been 
prepared,  phenyl  imidazoate,  PhNg,  being  identical  with 
the  diazobenzolimide  previously  described  by  G r i e s s.^ 


SUBSTITUTED    HYDRAZINES. 

Hydrazine  is  the  parent  of  a  large  and  important  class  of  bases 
generally  called  hydrazines,  one  member  of  which,  phenyl- 
hydrazine,  (CgHg)H]S'.NH2,  has  proved,  in  the  hands  of 
E.  Fischer  and  others,  a  reagent  of  the  highest  importance, 
numerous  recent  syntheses  in  the  sugar  group  having  been  effected 
through  its  aid.  By  replacing  a  second  atom  of  hydrogen  by  {e.g.) 
phenyl,  secondary  hydrazines  may  be  obtained  either 
symmetrical  like  hydrazobenzene,  (CgHg)HN.NH(CgH5), 
or  unsymmetrical  like  diphenylhydrazine,  (CeHg)2N.NH2. 
The  latter  class  resemble  the  tertiary  amines  (pnge  18)  in  their 
power  of  reacting  with  the  haloid  salts  of  the  alkyl  radicals 
(e.g.y  ethyl-iodide)  to  form  hydrazonium   compounds : — 

R2N.NH2  4- AkI  =  IAkR2N.NH2. 

The  hydrazines  containing  fatty  alkyl  radicals  are  liquids  boil- 
ing without  decomposition ;  those  of  the  aromatic  series  are  readily 
fusible  solids  or  oily  liquids,  and  are  partially  decomposed  on  dis- 
tillation. Hydrazine  itself  and  some  of  the  fatty  derivatives  are 
di-acid  bases ;  but  the  hydrazines  of  the  benzene  series  have  all 
monobasic  functions. 

The    hydrazines    closely    resemble    the    amines,    but    are    dis- 

1  From  the  ascertained  characters  of  imidazoic  acid,  and  its  analogy  to 
hydrocyanic  acid,  Mendelejeff  has  forniulated  some  very  interesting  prog- 
nostications. Just  as  ammonium  formate,  when  heated,  yields  formamide 
and  the  nitrile  HON,  so  ammonium  nitrate  decomposes  on  heating  with 
production  of  (an  intermediate  hypothetical  nitramide  and)  the  nitrile  N2O, 
nitrous  oxide. 

Similarly,  azoimide  may  be  regarded  as  the  nitrile  of  diammonium  ortho- 
nitrate,  thus  : — 

Formate,     .     .HCO.O.NH4  -  2H2O-H C.N  ;  hydrocyanic  acid. 

Meta-nitrate,   .  O.NO.O.NH4         -2H20  =  NO.N;  nitrous  oxide. 
Ortho-nitrate,  .  HO.NO:(O.NH4)2-4H20=.HN.N2 ;  imidazoic  acid. 

It  seems  not  improbable  that  the  ammonium  salt  of  imidazoic  acid, 
NH3.HN3,  may  prove  convertible  into  its  symmetrical  isomeride,  N.NH2.NH2.N, 
the  nitrile  of  triammonium  orthonitrate,  NO(ONH4)(ONH4)(ONH4), 
just  as  ammonium  cyanate  can  be  changed  into  urea.  The  existence  oi 
explosive,  coloured,  double  imidazoates  is  foretold  by  Mendelejeff. 


26  ETHYL-HYDRAZINE. 

tinguished  from  the  latter  by  their  capacity  of  reducing  Fehling's 
copper  solution,  in  many  instances  at  the  ordinary  temperature. 
The  product  of  the  oxidation  of  the  hydrazine  is  the  corresponding 
amine.  Thus,  diethyl-hydrazine,  (C2H5).2N.NH2,  is  oxidised 
to  diethyl-amine,  (02^.^)2^^' 

The  general  and  special  characters  of  the  hydrazines  are 
sufficiently  exemplified  by  two  typical  species,  ethyl- hydrazine 
and  phenyl-hydrazine. 

Ethyl-hydrazine.    CgHgN^  =  (C2H5)HN.NH2 . 

On  treating  diethyl-urea  with  nitrous  acid,  a  n i t r 0 s 0- 
compound  is  formed,  which  on  reduction  with  zinc-dust  and 
acetic  acid  is  converted  into  a  body  called  diethyl-semicar- 
b  a  z  i  d  e. 

„     fNH(CA)  fNH(C,H,)  |NH(C,H,) 

^"1NH(C,H,)     ^^  1  N(NO)(C,H,)      ^"  j  N(NH,)(C,H,) 

Diethyl-urea.  Nitroso-compound.  Diethyl-semicarbazide. 

This  last  body  decomposes,  on  heating  with  strong  hydrochloric 
acid,  into  ethyl-hydrazine,  ethylamine,  and  carbon 
dioxide : — 

NH(C2H5).CO.N(NH2)C2H,-hH20  =  HK(NH2)(C2H5)  + 
HNH(C2H5)  +  C02. 

The  ethylhydrazine  hydrochloride  is  less  soluble  than  the  cor- 
responding salt  of  ethylamine,  and  may  be  separated  from  it  b^ 
crystallisation. 

Ethylhydrazine  is  a  colourless,  mobile  liquid  of  ethereal  and 
faintly  ammoniacal  odour.  It  boils  at  100°,  and  distils  undecom- 
posed.  It  is  very  hygroscopic,  forming  white  fumes  with  moist 
air,  dissolves  in  water  and  alcohol  with  evolution  of  heat,  and 
corrodes  cork  and  caoutchouc. 

Ethylhydrazine  gives  Hofmann's  isonitrile  reaction  for  primary 
amines  with  chloroform  and  alcoholic  potash  (page  7).  Bromine 
decomposes  it  with  evolution  of  nitrogen,  and  it  is  also  decom- 
posed by  nitrogen  trioxide. 

Ethylhydrazine  is  a  very  powerful  deoxidising  agent.  It  reduces 
Fehling's  copper  solution  at  the  ordinary  temperature,  reduces 
argentic  oxide,  and  converts  oxide  of  mercury  into  mercuric 
e  t  h  i  d  e,  Hg(C2lIg)2.  It  yields  a  black  precipitate  with  Nessler's 
solution. 

Ethylhydrazine  reacts  with  aldehydes,  with  evolution  of  heat,  to 
form  ethyl-hydrazides,  R.CH:K'2H(C2H5). 


DiEtHVLHYDRAZINE.  27': 

Potassium  anhydrosulphite,  KgSgOy,  reacts  on  ethylhydrazine 
to  form  potassium  ethyl-hydrazine  sulphite, 

(C2H5)HN.NH(S03K), 
which,  on    treatment    with    mercuric  oxide,   gives    potassium 
diazo-ethane-sulphonate,  C2H5.N:  ^".(SOgK),  a  substance 
which  explodes  violently  when  warmed,  and  otherwise  resembles 
the  diazo-benzene-sulphonates  (Part  I.  page  137). 

Diethyl-hydrazine,  (C2H5)2N.NH2,  is  obtained  by  the  reduction  of 
the  nitroso-derivative  of  diethylamine  : — (02115)2^.^0  + 
2H2  =  (02H5)2N.NH2-|-H20.  It  boils  at  98°,  and  closely  resembles 
ethylhydrazine,  but  does  not  reduce  Fehling's  solution  unless  the 
liquid  is  heated.  It  unites  with  ethyl  iodide  to  form  the  body 
(02115)3X21121,  which  on  treatment  with  oxide  of  silver  yields  a 
strongly  alkaline  solution  oftriethylazonium  hydroxide, 
(02115)3^2112  OH,  a  powerful  base  analogous  to  tetrethylammonium 
hydroxide  (page  20),  and  which,  when  heated  with  water,  decom- 
poses into  ethylene,  diethyl- hydrazine,  and  water.  Mercuric  oxide, 
even  in  the  cold,  converts  diethyl-hydrazine  into  tetraethyl- 
tetrazone,  (02H5)2N.]S' : N.N(02H5)2,  a  colourless,  strongly  basic 
oil,  volatile  with  steam  and  yielding  a  metallic  mirror  with 
ammonio-nitrate  of  silver. 

Phenyl-hydrazine.    C6H8N2==(06H5)HKNH2. 

Phenyihydrazine  is  prepared  by  the  action  of  reducing  agents  on 
diazobenzene  compounds,  OgHgN  :  NX  (Part  I.  page  176). 
Thus  diazobenzene  chloride  may  be  reduced  by  the  calculated 
amount  of  stannous  chloride  and  hydrochloric  acid  ;  or  the  potassio- 
sulphite  with  zinc-dust  and  acetic  acid,  the  product  being  subse- 
quently decomposed  by  boiling  with  hydrochloric  acid : — 

C6H5.HKNH.SO3K  +  HCl  +  HgO  =  KHSO4  4-  06H5.HKNH2,H01.i 

•  Phenyihydrazine  is  a  yellow  oil  of  a  faint  aromatic  odour.  It 
solidifies  at  low  temperatures  to  a  crystalline  mass,  melts  at  23°,  and 
boils,  with  slight  change  and  evolution  of  ammonia,  at  241°-242°. 

^  Phenyihydrazine  is  best  obtained,  as  described  by  V.  M  e  y  e  r,  by  dissolving 
1000  parts  of  aniline  in  2000  parts  of  strong  hydrochloric  acid,  cooling  the 
solution  by  means  of  ice,  and  then  slowly  adding  an  ice-cold  solution  of  75 
parts  of  sodium  nitrite  in  400  c.c.  of  water.  To  the  cold  solution  of  diazo- 
benzene chloride,  CgHg. N  : N. CI,  so  obtained,  a  solution  of  450  parts  of 
stannous  chloride  in  an  equal  weight  of  hydrochloric  acid  is  then  added.  The 
mixture  soon  sets  to  a  white  cr3'stalline  pulp  of  phenyihydrazine  hydrochloride, 
CfiHoNHajHCl,  which  is  filtered  or  strained  off,  and  washed  with  a  mixture  of 
alcohol  and  ether.  The  free  base  is  obtained  by  dissolving  the  hydrochloride 
in  water,  adding  caustic  soda,  and  agitating  with  ether,  which  is  separated  and 
evaporated.     The  product  may  be  purified  by  distillation. 


28  PHENYLHYDRAZINE. 

It  volatilises  in  a  current  of  steam,  but  not  very  readily.  Phenyl - 
hydrazine  dissolves  sparingly  in  cold  water,  more  readily  in  hot,  and 
very  readily  in  alcohol,  ether,  chloroform,  and  benzene. 

Phenylhydrazine  is  readily  oxidisable,  and  becomes  red  and  ulti- 
mately dark  brown  on  exposure  to  air,  from  absorption  of  oxygen. 

Phenylhydrazine  has  well-marked  antiseptic  properties,  and  a 
O'l  per  cent,  solution  of  the  hydrochloride  has  been  recommended 
as  a  substitute  for  one  of  mercuric  chloride  of  equal  strength 
{Pharm.  Jour.,  [3],  xix.  608). 

Under  certain  undetermined  conditions,  contact  of  phenylhydra- 
zine with  the  skin  produces  troublesome  sores. 

Phenylhydrazine  has  well-marked  basic  properties,  and  forms 
well-crystallised  salts.  The  hydrocJiloride,  prepared  as  already 
described,  crystallises  from  hot  water  in  small,  thin,  lustrous  plates, 
and  is  almost  completely  precipitated  from  its  aqueous  solution  by 
concentrated  hydrochloric  acid,  a  reaction  by  which  phenylhydrazine 
may  be  readily  separated  from  aniline  and  several  other  bases. 

Solutions  of  the  hydrochloride  and  other  salts  of  phenylhydrazine 
act  as  powerful  reducing  agents.  They  reduce  the  salts  of  silver, 
mercury,  gold,  and  platinum  in  the  cold.  Fre&hly-precipitated 
mercuric  oxide  is  reduced,  a  salt  of  diazobenzene  being  reproduced. 
Fehling's  solution  is  reduced  in  the  cold,  with  evolution  of  nitrogen 
and  precipitation  of  cuprous  oxide,  aniline  and  benzene  being 
simultaneously  formed. 

If  phenylhydrazine  hydrochloride  be  treated  with  a  cold  solution 
of  potassium  nitrite,  a  nitroso-compound,  CgH5(NO)N.NH2 , 
separates  in  yellow  flocks,  which,  on  treatment  with  phenol  and 
strong  sulphuric  acid,  yield  a  brown  solution,  changing  to  green 
and  blue.  This  reaction,  observed  by  Liebermann,  is  common 
to  all  nitroso-derivatives. 

Phenylhydrazine  combines  directly  with  carbon  dioxide,  carbon 
disulphide,  and  cyanogen.  The  sul  phonic  acid  (para)  is  em- 
ployed for  the  preparation  of  tartrazin  (Part  II.  page  288)  and 
otlier  dyes. 

Phenylhydrazides.  The  acetyl-derivative  of  phenylhydrazine, 
Cgll5.H^^.NH(C2H30),  which  may  be  regarded  as  acet-phenyl- 
hydrazide,  has  powerful  antipyretic  properties,  and  has  been 
introduced  into  German  pharmacy  under  the  name  of  "  hydracetin." 
The  same  substance  is  said  to  be  the  active  ingredient  of  the 
preparation  known  as  "p  y  r  o  d  i  n  e"  {Pltarm.  Journ.,  [3],  xix.  425, 
508,  1049).  Both  substances  seem  to  be  uncertain  in  their  action 
and  dangerous  in  use  ;  in  fact,  hydracetin  is  reported  by  R  e  n  v  e  r  s 
to  be  a  direct  blood-poison,  the  antithermic  properties  of  which 
are  really  due  to  destruction  of  the  red  cori)Uscles. 


PHENYLHYDRAZIDES.  29 

"  Orthine"  is  the  name  given  by  R  Robert  to  a  body  having 
the  constitution  of  an  orthohydrazine-para hydroxy- 
benzoic    acid  : — 

r  (OH)(i) 

i(CO.OH>'^). 

The  free  base  is  very  unstable ;  but  the  hydrochloride  is  stable, 
reduces  the  persalts  of  the  heavy  metals,  and  possesses  a  marked 
antiseptic  action. 

Phenylhydrazine  in  aqueous  solution  reacts  very  readily  with 
the  hydroxy-acids  of  the  sugar  group  (e.g.,  gluconic  and  galac- 
tonic  acids,  C5Hg(OH)5.COOH;  arabinose-carboxylic  acid,  CgHj207) 
with  elimination  of  water,  to  form  crystalline  phenylhydrazides, 
K  C0.HN.NH(CgH5).  They  are  prepared  by  treating  a  10  per  cent, 
solution  of  the  acid  or  its  lactone  with  a  moderate  excess  of  phenyl- 
hydrazine  and  an  equal  quantity  of  50  per  cent,  acetic  acid,  and 
heating  the  mixture  to  100°  for  80  to  120  minutes.  The  hydrazide 
sometimes  crystallises  from  the  hot  solution,  but  more  usually 
separates  on  cooling.  Any  free  mineral  acid  should  be  neutralised 
by  soda  before  adding  the  hydrazine,  and  bromides,  chlorides,  and 
sulphates  should  be  got  rid  of  by  adding  acetate  of  lead.  If  sugar 
be  present,  the  osazone  formed  can  usually  be  separated  from  the 
hydrazide  by  crystallisation  from  hot  water.  The  products  are 
beautifully  crystalline,  those  derived  from  monobasic  acids  being 
but  little  soluble  in  cold,  and  only  with  difficulty  soluble  in  hot 
water,  while  those  from  polybasic  acids  (e.g.,  saccharic,  metasaccharic, 
and  mucic)  are  still  less  readily  soluble.  The  compounds  from 
isomeric  acids  usually  present  a  close  resemblance  in  their  physical 
properties,  but  the  acids  from  which  they  are  derived  can  be 
regenerated  (in  a  pure  state)  by  boiling  the  hydrazide  for  half  an 
hour  with  thirty  volumes  of  10  per  cent,  baryta  water,  which  treat- 
ment hydrolyses  them  completely.  From  the  product,  the  phenyl- 
hydrazine  is  extracted  by  agitation  with  ether,  and  the  aqueous 
liquid,  with  any  precipitate  which  may  have  been  formed,  is  boiled 
and  treated  with  sulphuric  acid  in  quantity  sufficient  to  precipitate 
the  barium  as  BaSO^.  The  filtered  liquid  yields  the  free  acid  or 
lactone  on  evaporation  (Fischer  and  Passmore,  Ber.,  xxii. 
2728;  Jour.  Chem.  >Soc.,  Iviii.  152). 

The  hydrazides  are  colourless  and  readily  hydrolysed  by  'alkalies 
and  baryta.  They  can  be  readily  distinguished  from  the  hydra- 
zones  by  the  reddish  violet  coloration  they  give  when  dissolved 
in  strong  sulphuric  acid  and  treated  with  a  drop  of  ferric  chloride 
solution. 


30  PHENYLHYDRAZINE   DERIVATIVES. 

Hydrazones.  Phenylhydraziiie  behaves  in  a  highly  interesting 
manner  with  bodies  having  the  constitution  of  aldehydes  and 
ketones,  with  whicl.  it  reacts  with  elimination  of  water  to  form 
compounds  called  hydrazones.  Most  of  the  bodies  of  this  class 
are  solid  and  crystalline,  and  therefore  well  suited  for  the  recognition 
of  the  aldehydes  or  ketones  producing  them.  The  reaction  appears 
to  be  general  for  bodies  containing  the  carbonyl  group,  CO. 
The  reaction  is  sometimes  complicated  by  the  presence  of  other 
reactive  groups.  Thus  compounds  containing  the  a-ke tone- 
alcohol  grou p, —  CH(OH).CO — ,  react  in  the  cold  with  only 
one  molecule  of  phenylhydrazine  to  form  colourless  compounds 
containing  the  group:— CH(OH).C.(N.NHC6H5)—. 

OsAZONES.  When  the  compound  thus  formed  is  heated  with 
excess  of  phenylhydrazine,  the  alcohol  group  undergoes  dehydro- 
genisation,  reacting  at  the  same  time  with  a  second  molecule  of 
phenylhydrazine  and  giving  rise  to  a  yellow  compound  containing 
the  complex  group,— C(N.NHC6H5).C(N.NHC6H5)—.  Compounds 
of  this  kind,  in  which  two  hydrazine-residues  are  attached  to  two 
contiguous  carbon-atoms,  are  called  osazones,  and  maybe  obtained 
directly  by  the  action  of  phenylhydrazine  on  the  di-ketones.  They 
are  of  interest  in  connection  with  the  carbohydrates,  which  may 
frequently  be  recognised  by  means  of  their  characteristic  osazones 
(E.  Fischer,  Ber.^  xvii.  579;  xx.  821).  VonJaksch  {Jour. 
Chem.  Soc,  1.  744)  recommends  a  solution  of  phenylhydrazine  hydro- 
chloride containing  sodium  acetate  for  the  detection  of  sugar  in  urine. 

Pyrazolines.  An  unsaturated  hydrocarbon  group  {e.g.,  a  1 1  y  1, 
CgHg),  if  contiguous  to  the  carbonyl  group,  may  also  react  with 
phenylhydrazine  : —  -^ -j^  ^  g 

CH2:CH.COH-hC6H5.HKNH2  =  H20-f-  |1  |     ^    '^ 

Acrolein.  Phenylhydrazine.       Water.      CH.CH  .CH 

Phenyl-pjTazoline. 

Pyrazolones. 

The  pyrazolones  are  derivatives  of  a  body  of  the  formula 
C3H4N2O ,  the  synthesis  of  which  has  been  effected  by  Balbiano 
{Ber.,  xxiii.  1103).  The  relationship  of  pyrazolone  to  pyrazol, 
pyrazoline,  and  pyrazine  is  shown  by  the  following  formulae : — 

Pyrazol.  Pyrazoline.  Pyrazolone.  Pprazine.i 

^  This  body  must  not  be  confounded  with  p  i  a  z  i  n  e,  which  was  formerly 
called  pyrazine,  and  probably  has  the  constitution : — 

/CH:CH\ 

^CH:CH^ 
(See  A.  T.  Mason,  Jour.  Chem.  Soc,  Iv.  97.) 


PYRAZOLONES.  81 

Phenyl-pyrazolone,  CgHg.CgHgNgO,  is  obtained  by  heating 
phenylhydrazine  and  iodopropionic  acid  together  to  100°,  and  treat- 
ing the  product,  in  chloroform  solution,  with  mercuric  oxide. 

Phenyl-methylpyrazolone,  CioHjQNgO ; 

CHg.C — CH2 

When  phenylhydrazine  is  added  to  ethylic  aceto-acetate, 
CH3.CO.CH2.CO.O(C2H5),  the  two  bodies  react  in  the  cold,  with 
elimination  of  water,  to  form  CH3.C(N.NHPh)CH2.CO.O(C2H5)  } 
On  heating,  the  hydrazone  thus  formed  splits  up  into  alcohol  and 
phenyl-methylpyrazolone,  a  body  which  was  originally  regarded  by 
its  discoverer,  Knorr,  as  a  m  e  thy  1-oxy  quin  izine. 

To  prepare  phenyl-methylpyrazolone,  100  parts  of  phenyl-hydra- 
zine are  added  to  125  of  ethyl  aceto-acetate,  the  water  which  forms 
is  separated,  and  the  oily  product  is  heated  for  two  hours  on  a 
water-bath,  until  a  portion  is  found  to  solidify  on  cooling,  or  on 
the  addition  of  ether.  The  warm  mass  is  poured  into  and  stirred 
with  ether,  which  removes  colouring  matter,  and  the  white  crystal- 
line product  washed  with  ether,  and  dried  at  100°.  The  yield  is 
quantitative  and  the  product  pure.  It  is  almost  insoluble  in  cold 
water,  ether,  and  petroleum  spirit,  more  readily  in  hot  water,  and 
easily  in  alcohol.  It  crystallises  from  hot  water  or  alcohol  in  hard 
brilliant  prisms.^    The  hydrochloride,  Cj^qK^qN2^)^^^'^^2^'  melts 

^  Antithermin.  When  an  aqueous  solution  of  levulinic  acid  (aceto-pro- 
pionic  acid),  CH3.CO.CH2.CH2.COOH,  is  added  to  an  equivalent  amount  of 
phenylhydrazine,  dissolved  in  dilute  acetic  acid,  a  yellow  precipitate  is  produced 
of  the  h  y  d  r  a  z  0  n  e,  CHgCCN.  NHPh).  CHo.  CHg.  COOH .  When  recrystallised 
from  alcohol,  this  body  forms  large  colourless,  odourless  crystals  of  a  slight  bitter 
taste,  melting  at  98°-99"',  and  nearly  insoluble  in  water,  but  soluble  in  alcohol, 
ether,  and  dilute  acid.  It  has  met  with  a  limited  application  as  an  antipyretic 
under  the  name  of  antithermin.  It  is  decomposed  by  alkalies  with 
liberation  of  phenylhydrazine,  to  which  fact  it  probably  owes  its  physiological 
activity. 

^  When  a  mixture  of  phenylmethyl-pyrazolone  and  phenylhydrazine  is 
heated  to  boiling,  disphenyl-methylpyrazolone,  C2oH]8N^402,  is 
formed.  Heated  with  methyl  alcohol  or  methyl  iodide  it  yields  dianti- 
p  y  r  i  n  e,  C22H  22^402*  melting  at  245°,  and  distinguished  from  antipyrine  by  its 
sparing  solubility  in  water  and  the  melting-point  of  its  picrate  (161").  When 
the  body  C20H18N4O2  is  treated  in  alkaline  solution  with  excess  of  sodium 
nitrite,  and  the  mixture  poured  into  dilute  sulphuric  acid,  pyrazol-blue, 
C2oHjg'N'402,  separates  in  flocks.  When  crystallised  from  chloroform  it  forms 
blue  needles,  insoluble  iu  water,  dilute  acids,  and  alkalies,  and  only  sparingly 
soluble  in  alcohol  and  ether.     Its  solutions  in  chloroform  and  strong  sulphuric 


32  PHENYL-DIMETHYLPYRAZOLONE. 

at  96°,  ai)d  the  cMoropIatinate,  (CioHioN^O)2H2PtCl6  +  4H20,  in 
prisms  melting  at  110°.  Phenyl-methylpyrazolone  yields  crystal- 
line precipitates  with  salts  of  many  of  the  heavy  metals.  With 
silver  nitrate  an  aqueous  solution  gives  crystals  of  CioHgAgN20  + 
^10^10^2^'  "^^^  ultramarine  cobalt  compound  and  the  orange- 
yellow  uranium  salt  are  especially  characteristic. 

Phenyl-dimethylpyrazolonb.     Antipyrine.     Phenazonb. 

C11H12N2O  =  C3N2H(C6H5)(CH3)20     [Ph  :  Me  :  Me  =  1  :  2  :  3] ;  1 

or,  00.^  NPh.NMe  f  '  ""''  ^6^5-^  •  ^  CO CH  :l\ 

When  phenyl-methylpyrazolone  is  heated  with  methyl  iodide,  a 
further  substitution  takes  place,  with  formation  of  phenyl-dimethyl- 
pyrazolone,  a  substance  known  generally  as  "  a  n  t  i  p  y  r  i  n  e,"  less 
commonly  as  "analgesi n,"  and  called  in  the  additions  to  the 
British  Pharmacopoeia  (1890),  phenazorie.  It  is  official  in  the 
German  Pharmacopoeia  of  1890  under  the  name  of  Antipyrinum. 

Antipyrine  is  prepared  by  heating  equal  parts  of  phenyl-methyl- 
pyrazolone, methyl  iodide,  and  methyl  alcohol  to  100°  in  a  closed 
vessel.  The  dark  product  is  decolorised  by  boiling  with  sulphurous 
acid,  the  alcohol  distilled  off,  and  the  residue  shaken  with  strong 
soda,  when  the  base  separates  as  a  heavy  oil.  This  is  separated 
and  treated  with  ether,  in  which  it  is  sparingly  soluble.  On 
separating  the  ether  and  evaporating  off  the  solvent,  the  antipyrine 
is  obtained  as  a  mass  of  crystals  which  are  purified  by  recrystallisa- 
tion  from  toluene. 

Antipyrine  forms  small,  lustrous,  rhombic  needles  or  plates, 
which  are  odourless,  but  have  a  somewhat  bitter  taste.  When 
perfectly  anhydrous  it  melts  at  110°  to  112°  {B.P.,  110°;  G.P., 
113°),  but  on  exposure  to  air  takes  up  a  small  proportion  (0'6  per 
cent.)  of  water,  and  in  that  state  melts  at  105°-107°  C.  The 
hygroscopic  water  may  be  driven  off  by  exposing  the  substance  to 
a  temperature  of  100°,  when  the  original  melting-point  is  restored. 

Antipyrine  is  soluble  in  about  its  own  weight  of  cold  water,  and 
in  less  than  half  its  weight  of  boiling  water.     It  dissolves  in  twice 

acid  has  an  indigo-blue  colour,  and  gives  an  absorption-spectrum  resembling 
that  of  indigo.  It  is  not  a  substantive  dye,  is  decomposed  by  strong  alkalies, 
decolorised  by  chlorine  and  nitric  acid,  and  converted  into  disphenyl-methyl- 
pyrazolone  by  reducing  agents. 

1  Two  isomers  of  antipyrine  have  been  prepared,  and  others  are  capable  of 
existing.  The  known  isomers  differ  from  antipyrine  by  being  less  soluble  in 
water,  not  yielding  nitroso-derivatives,  and  by  giving  methyl-aniline  either 
when  distilled  with  zinc-dust  or  heated  with  hydrochloiic  acid  to  200°  undei 
pressure. 


ANTIPYKINE.  33 

its  weight  of  absolute  alcohol,  but  in  little  more  than  its  own 
weight  of  rectified  spirit,  Antipyrine  is  soluble  in  an  equal  weight 
of  amylic  alcohol,  and  in  one  and  a  half  times  its  weight  of  chloro- 
form, but  requires  about  fifty  parts  of  ether  for  solution,  is 
difficultly  soluble  in  benzene,  and  nearly  insoluble  in  petroleum 
spirit. 

On  adding  strong  caustic  soda  to  an  aqueous  solution  of  anti- 
pyrine, the  base  separates  as  a  milky  precipitate,  which  speedily 
collects  into  oily  globules.  On  adding  a  little  ether,  these  imme- 
diately solidify  to  white  crystals  without  appreciably  dissolving,  but 
they  dissolve  instantly  on  adding  chloroform  ( J.  C.  W  a  t  e  r  h  o  u  s  e). 

An  aqueous  solution  of  antipyrine  exhibits  no  alkaline  reaction 
with  litmus  or  phenol-phthalein,  but  destroys  the  red  colour  of  an 
acidulated  solution  of  methyl-orange.  Free  antipyrine  may  be 
determined  with  accuracy  by  titration  in  aqueous  or  alcoholic  solu- 
tion with  methyl-orange. 

Antipyrine  is  a  strong  monovalent  base.  Its  salts,  most  of 
which  are  soluble,  do  not  readily  crystallise,  with  the  exception  of 
the  picrate  (melting  at  188°);  the  ferrocyanide  {C-^-Jl-^^jd\^ 
H^Cfy,  which  forms  a  crystalline  precipitate ;  the  chloroplatinate, 
(CjiHj2N2^)2»^2-P^^^6  +  2-'^2^'  which  forms  yellowish-red  prisms 
melting  at  about  200° ;  and  the  salicylate  (page  37). 

When  antipyrine  is  heated  with  hydrochloric  acid  under  pressure 
to  200°,  it  suffers  complete  decomposition,  yielding  much  aniline 
and  a  small  quantity  of  methylamine,  besides  other  products. 
On  distillation  with  zinc-dust  it  yields  benzene,  aniline,  a 
base  boiling  at  86°-87°,  and  other  products. 

Antipyrine  is  unchanged  by  treatment  with  reducing  agents  in 
the  wet  way,  but  with  oxidising  agents  it  gives  a  series  of  interest- 
ing reactions  (Gay  and  Fortun^,  Pharm.  Jour.,  [3],  xviii. 
1066).  Thus  when  boiled  with  potassium  chlorate  and  hydro- 
chloric acid,  antipyrine  gives  a  reddish-yellow  liquid,  which  on 
cooling  deposits  bright-red  oily  globules,  taken  up  by  chloroform 
with  greenish-yellow  colour.  A  solution  of  bleaching  powder  pro- 
duces no  change  in  the  cold,  but  on  heating  a  brick-red  precipitate 
is  formed,  and  the  liquid  is  coloured  yellow.  Sodium  hypochlorite 
is  said  to  give  the  yellow  coloration  on  heating,  without  any  pre- 
cipitate being  formed.  Chlorine-water  produces  no  change,  and 
bromine-water  a  light  yellow  precipitate,  dissolving  on  heating. 
Potassium  bichromate  and  permanganate  are  reduced  by  acid  solu- 
tions of  antipyrine. 

When  a  solution  of  iodine  in  iodide  of  potassium  is  added  to  a 
solution  of  antipyrine,  a  precipitate  is  formed  which  disappears  on 
agitation,  leaving  the  solution  colourless ;  but  on  further  addition  of 

VOL.  III.  PART  II.  0 


34  REACTIONS   OF   ANTIPYRINE. 

the  reagent  a  permanent  brick-red  precipitate  is  produced,  per- 
ceptible in  a  dilution  of  1  in  20,000.  According  to  Manseau 
(Pharm.  Jour.^  [3],  xx.  162),  the  point  at  which  a  permanent 
precipitate  is  formed  is  perfectly  definite,  and  he  suggests  that 
the  purity  of  a  sample  can  be  ascertained  by  titration  with  a 
standard  solution  of  iodine.  Millard  and  Stark  {Pharm. 
Jour.,  [3],  XX.  863)  find  that  the  point  of  permanent  precipita- 
tion depends  to  a  marked  degree  on  the  dilution  of  the  antipyrine 
solution.  Thus  in  a  1  per  cent,  solution,  1  gramme  of  antipyrine 
gives  a  permanent  precipitate  after  the  addition  of  3 '9  c.c.  of 
decinormal  iodine,  while  with  twice  the  volume  of  water  7*2  c.c. 
are  required.  The  authors  state  that  more  concordant  results  are 
obtainable  by  using  starch  as  an  indicator  of  the  end  of  the  re- 
action. They  dissolve  0*5  gramme  of  the  sample  of  antipyrine  in 
200  CO.  of  water,  add  plenty  of  starch  solution,  and  then  drop  in 
decinormal  iodine  solution  gradually  until  a  distinct  blue  coloration 
is  obtained,  which  does  not  disappear  on  vigorously  shaking  or 
stirring  the  mixture.  E.  M  ti  n  z  e  r  has  described  an  iodo-anti- 
pyrine,  Cj^H^jINgO,  which  forms  colourless,  tasteless  needles,  melt- 
ing at  160°. 

An  acid  solution  of  mercuric  nitrate  gives  a  white  precipitate 
with  a  solution  of  antipyrine.  2  c.c.  of  Millon's  reagent  and 
4  c.c.  of  a  1  per  cent,  (neutral)  solution  of  antipyrine  give  a 
white  precipitate  in  a  yellow  liquid ;  in  a  solution  acid  with 
hydrochloric  acid,  a  yellow  precipitate  in  an  orange-yellow  liquid, 
the  precipitate  eventually  becoming  red.  In  a  solution  ten  times 
more  dilute  a  yellow  precipitate  and  green  liquid  result,  and  in  an 
acid  solution  of  1  part  of  antipyrine  in  20,000,  a  white  precipitate 
and  yellow  liquid.  1  c.c.  of  a  saturated  solution  of  mercurous 
nitrate  added  to  twice  its  measure  of  a  1  per  cent,  solution  of 
antipyrine  gives  a  yellow  precipitate  floating  on  a  blood-red  liquid. 

If  antipyrine  be  heated  with  strong  nitric  acid  till  reaction 
commences,  and  the  liquid  be  then  allowed  to  cool,  a  fine  purple 
coloration  is  produced;  on  adding  water  a  violet  precipitate  is 
thrown  down,  and  the  filtered  liquid  is  purple-red. 

Nitroso-anti'pyrine.  Several  of  the  foregoing  reactions  are 
probably  due  to  the  presence  of  nitrous  acid,  which  (if  added  in 
the  form  of  red  fuming  nitric  acid)  gives  with  a  1  per  cent, 
solution  of  antipyrine  a  beautiful  green  coloration,  still  perceptible 
when  diluted  to  1  in  20,000 ;  when  the  liquid  is  heated  it 
becomes  purple-red.  In  strong  solutions  a  copious  formation 
of  small,  green,  needle-shaped  crystals  occurs.  These  consist  of 
isonitroso- antipyrine,  CiiII;^/N0)]S'20,  and  are  best 
obtained  by  adding  a  solution  of   sodium  nitrite  to  a  solution 


NITROSO-ANTIPYRINE.  35 

of  antipyrine  in  acidulated  water.  The  liquid  at  once  becomes 
bluish  green  in  colour,  and  an  abundant  formation  of  crystals 
speedily  occurs.  These  may  be  washed  with  cold  water,  and 
dried  at  the  ordinary  temperature.^  Mtroso-antipyrine  explodes 
when  heated  to  about  200°,  is  nearly  insoluble  in  water  and 
dilute  acids,  soluble  in  alkalies  and  in  acetic  acid,  moderately 
soluble  in  alcohol,  and  sparingly  in  chloroform  and  ether.  By 
treatment  with  zinc  and  acetic  acid  it  is  converted  into  an  oily 
base. 

The  green  coloration  of  antipyrine  with  nitrous  acid  is  delicate 
and,  to  a  certain  extent,  characteristic,  but  is  common  to  all 
pyrazolones.  A.  C.  Stark  recommends  that  the  test  should  be 
applied  by  dissolving  potassium  nitrite  in  a  test-tube  in  a  little 
water,  adding  excess  of  strong  sulphuric  acid,  and  then  filling 
the  tube  with  the  liquid  to  be  tested. 

Antipyrine  dissolves  without  colour  in  pure  anhydrous  ethyl 
nitrite,  but  a  green  colour  is  immediately  developed  on  addition 
of  water.  When  antipyrine  is  added  to  spirit  of  nitrous  ether 
containing  free  acid,  the  mixture  rapidly  acquires  a  dark-green 
tint,  and  green  needles  of  nitroso-antipyrine  separate.  The 
reaction  (which  does  not  occur  if  any  free  acid  be  neutralised 
by  potassium  bicarbonate)  derives  practical  importance  from 
the  fact  that  spirit  of  nitrous  ether  and  antipyrine  are  not 
infrequently  dispensed  in  conjunction.  A  mixture  of  the  kind 
is  alleged  to  have  been  fatal  to  the  patient,  but  it  is  very 
doubtful  if  the  nitroso-derivative  of  antipyrine  was  the  cause  of 
death;  for  direct  exhibition  of  the  compound  to  a  small  rabbit, 
both  hypodermically  and  by  the  stomach,  in  doses  commencing 
at  J  grain,  and  gradually  increased  to  4  grains,  produced  no 
perceptible  toxic  effect  {Fharm.  Jour.,  [3],  xviii.  1085).  Similar 
experiments  have  been  made  on  dogs  (Pharm.  Jour.,  [3],  xix. 
807). 

Antipyrine  gives  a  very  delicate  and  characteristic  reaction 
with  ferric  chloride,  which,  in  a  1  per  cent,  solution,  produces 
a  blood-red  coloration.  The  reaction  is  still  very  distinct  in  a 
solution  of  1  in  2000,  and  perceptible  at  a  dilution  of  1  in 
50,000.  The  red  coloration  is  destroyed  by  excess  of  mineral 
acids.  The  reaction  is  at  once  given  by  urine  containing  anti- 
pyrine. 

On  mixing  cold  aqueous  solutions  of  antipyrine  and  mercuric 

^  The  liquid  filtered  from  the  crystals  gradually  changes  colour  from 
green  to  brown,  and  after  standing  for  some  hours  is  found  to  smell  of 
hydrocyanic  acid,  but  the  quantity  of  this  body  formed  appears  to  be 
very  minute  (Wood  and  Marshall,  Fharm.  Jour.,  [3],  xixi  806^ 


36  REACTIONS  OF  ANTIPYRINE. 

chloride,  a  white  precipitate  is  formed.  On  boiling  the  liquid 
this  disappears,  but  on  continued  boiling  a  brown  resinoid  sub- 
stance is  deposited,  which,  when  separated,  is  found  to  be  soluble 
in  hot  alcohol  and  in  nitric  acid,  and  is  coloured  scarlet  by  strong 
sulphuric  acid. 

Antipyrine  reacts  in  the  general  manner  of  alkaloids.  Thus, 
in  acid  solutions  it  gives  a  yellowish-white  precipitate  with 
Mayer's  reagent,  and  the  same  with  Marm^'s  test  (potassio- 
cadmium  iodide) ;  a  green  precipitate  changing  to  orange-red 
with  potassio-iodide  of  bismuth;  an  abundant  reddish-yellow 
precipitate  with  Nessler's  reagent ;  a  white  with  phosphomolybdate 
of  sodium ;  and  an  abundant  white  precipitate  with  tannin.^ 

According  to  the  German  Pharmaco;pceia,  the  solution  of 
antipyrine  in  two  parts  of  water  should  be  neutral,  free  from 
acrid  taste,  and  not  changed  by  sulphuretted  hydrogen  water. 
A  2  per  cent,  solution  should  give  a  white  precipitate  with 
tannin;  and  on  addition  of  two  drops  of  fuming  nitric  acid 
to  2  c.c.  of  the  solution,  a  green  coloration  should  occur, 
changed  to  red  on  boiling  and  adding  another  drop  of  nitric 
acid.  2  c.c.  of  a  0'2  per  cent,  solution  gives  a  deep  red  colour 
with  a  drop  of  ferric  chloride  solution,  changed  to  bright  yellow 
on  adding  10  drops  of  sulphuric  acid.  Similar  tests  are  given 
in  the  additions  (1890)  to  the  British  Pharmacopoeia,  in  which 
antipyrine  receives  the  designation  "phenazone."^ 

Antipyrine  has  now  an  established  position  and  wide  applica- 
tion in  medicine.  Although  originally  introduced  as  a  febrifuge, 
it  is  taking  a  still  higher  place  as  an  anodyne.  Given  in  10 
to  20  grain  doses  in  cases  of  bilious  and  nervous  headache,  it 
often  effects  a  remarkably  rapid  and  perfect  cure.  It  has  been 
usefully  injected  hypodermically  in  8-grain  doses  as  a  substitute 
for  morphia;  and  for  the  relief  of  pain  in  acute  and  chronic 
gout,  neuralgia,  sciatica,  &c.  The  subcutaneous  injection  of 
antipyrine  is  said  not  to  be  followed  by  drowsiness,  vomiting, 
or  excitement.  It  is  stated  to  be  almost  a  specific  in  puerpural 
fever.  It  has  been  found  valuable  as  a  haemostatic,  and  has 
proved  successful  in  some  cases  of  sea-sickness,  but  by  no 
means  invariably.     Antipyrine   causes    an    almost    immediate   re- 

^  The  reactions  described  in  the  text  sufficiently  indicate  the  pharmaceutical 
preparations  with  which  antipyrine  is  incompatible.  Thus  it  should  not  be 
dispensed  in  a  mixture  with  nitric  acid,  nitrites,  chloral  hydrate,  solid  sodium 
salicylate,  carbolic  acid,  tannin,  iodine,  mercuric  chloride,  salts  of  iron, 
permanganates,  or  tinctures  or  infusions  of  catechu,  cinchona,  roses,  galls, 
rhubarb,  &c.  (see  Millard  and  Stark,  Pharm.  Jour.,  [3],  xx.  860). 

2  Antipyrine  has  been  adulterated  with  acetanilide  (see  page  72). 


ANTIPYRINE  SALICYLATE.  37 

duction  in  the  temperature  of  the  body  (apparently  from  its 
influence  on  the  brain-centres  regulating  the  temperature),  the 
effect  continuing  from  four  to  six  hours.  It  induces  sweat- 
ing and  feeble  pulse,  and  in  excessive  doses,  or  even  small 
doses  in  certain  cases,  an  eruption  resembling  nettle-rash,  occa- 
sionally with  vomiting  and  collapse.^  Atropine  has  been  found  to 
act  promptly  as  an  antidote. 

Antipyrine  may  be  detected  in  the  urine  for  eighteen  to 
twenty-four  hours  after  it  is  taken  by  the  stomach,  but  can  be 
detected  only  for  a  few  hours  in  the  different  organs.  It  has 
been  detected,  after  putrefaction  for  a  fortnight,  in  animals  killed 
within  two  hours  after  its  administration,  either  by  the  stomach 
or  hypodermically. 

Antipyrine  is  readily  extracted  from  animal  matters,  by  rendering 
the  liquid  ammoniacal  and  agitating  it  with  chloroform  or  amylic 
alcohol. 

Antipyrine  Salicylate,  CiiH^gNgOjCyHgOa.  If  salicylic  acid  be 
gradually  added  to  a  dilute  boiling  solution  of  antipyrine,  anti- 
pyrine salicylate  separates  as  a  yellowish  oil.  The  compound  can 
be  more  conveniently  prepared  by  heating  equivalent  proportions 
of  antipyrine  and  salicylic  acid  with  a  little  water  to  90°,  or  by 
shaking  together  an  aqueous  solution  of  antipyrine  with  an  ethereal 
solution  of  salicylic  acid,  when  the  salt  separates  in  fine  crystals. 
Antipyrine  salicylate  melts  at  89°-90°  C,  and  decomposes  at  a 
somewhat  higher  temperature,  dissolves  in  250  parts  of  cold  water 
more  freely  in  hot,  and  readily  in  alcohol,  ether,  chloroform,  and 
carbon  disulphide.  The  aqueous  solution  is  faintly  acid  in  reaction, 
and  has  a  sweet  taste  and  bitter  after-taste.  It  gives  a  violet  colora- 
tion with  ferric  chloride,  and  green  with  nitrous  acid.  Salicylate 
of  antipyrine  has  been  employed  with  favourable  results  in  medi- 
cine under  the  name  of  "  s  a  1  i  p  y  r  i  n."  A  mixture  of  antipyrine 
and  salicylate  of  sodium  gradually  changes  to  an  oily  liquid  on  ex- 
posure to  air.  The  change,  which  does  not  occur  in  a  closed  bottle, 
appears  to  be  simply  due  to  absorption  of  moisture  by  the  salicylate 
and  the  solution  of  the  antipyrine  in  the  water  thus  absorbed. 

Antipyrine  becomes  pasty  when  mixed  with  betanaphthol,  and 
appears  to  form  a  compound  with  phenol.  Under  the  name  of 
"resopyrin,"  Portes  has  described  a  compound  obtained  by 
mixing  solutions  of  molecular  proportions  of  resorcinol  and  anti- 
pyrine. It  crystallises  in  oblique  rhombic  prisms,  insoluble  in 
water  but  soluble  in  alcohol. 

^  The  exhibition  of  antipyrine  is  unsafe  when  the  heart  is  weak.  A  case 
where  severe  symptoms  were  produced  by  a  dose  of  1  gramme  has  been 
recorded  bySchwabe  {Pharm.  Jour.,  [3],  xx.  1059). 


38  CHLORAL- ANTIPYRINE. 

CMoral-Antipynne,  CiiHij(C2H2C]30)]N'20.  When  dilute  solu- 
tions of  chloral  hydrate  and  antipyrine  are  mixed  no  perceptible 
reaction  occurs,  but  on  concentrating  the  liquid,  or  on  mixing  strong 
solutions  of  the  two  substances,  a  separation  of  oily  globules  takes 
place,  and  these  immediately  or  gradually  change  to  a  mass  of 
crystals  of  chloral -antipyrine.  The  same  substance  may  be  obtained 
by  heating  molecular  proportions  of  chloral  hydrate  (165"5  parts) 
and  antipyrine  (188  parts)  to  110°-115°  C.  The  reaction  consists 
in  elimination  of  water  and  substitution  of  the  group  CCl3.CH(0E[) 
for  one  of  the  hydrogen  atoms  of  the  antipyrine  ;^  but  whether  the 
replaced  atom  is  one  of  those  of  the  methyl  groups,  or  the  hydrogen 
atom  of  the  CH  group,  is  not  definitely  decided  (compare  Pharm. 
Jour.,  [3],  XX.  page  862  with  page  889). 

Chloral-antipyrine,  also  called  h  y  p  n  a  1,  crystallises  from  alcohol 
in  hard  scales  and  from  water  in  transparent  rhombs.  It  melts  at 
67°-68°,  is  almost  odourless,  and  has  a  saline  taste  with  an  after- 
taste suggestive  of  chloral.  It  is  only  slightly  soluble  in  cold 
alcohol,  ether,  and  chloroform,  but  somewhat  more  soluble  in  boil- 
ing alcohol,  and  is  dissolved  by  about  eight  parts  of  warm  water. 
The  solution  reduces  Fehling's  solution  on  warming,  gives  the 
blood-red  reaction  of  antipyrine  with  ferric  chloride,  and  yields 
chloroform  when  heated  with  dilute  caustic  alkali.  When  chloral- 
antipyrine  is  kept  in  a  melted  state  for  some  time,  it  deposits 
crystals  of  a  dehydration  compound,  which  is  insoluble  in  water, 
melts  at  186°— 187°,  and  gives  no  colour-reaction  with  ferric 
chloride.  According  to  Eeuter  {Pharm.  Jour.^  [3],  xx.  602) 
chloral-antipyrine  is  physiologically  inert,  but  B  a  r  d  e  t  found  doses 
of  1  gramme  to  induce  sleep  as  readily  as  chloral  hydrate,  while  in 
cases  of  insomnia  caused  by  pain  it  seemed  to  have  the  same 
anodyne  effect  as  antipyrine.  Schmidt  finds  the  monochloral- 
derivative  to  have  more  decided  soporific  effect  and  a  less  deleterious 
influence  on  the  circulation  than  antipyrine. 

Bichloral- Antipyrine  is  obtained  by  heating  antipyrine  with 
excess  of  a  strong  solution  of  chloral  hydrate,  when  an  oily  layer 
is  formed,  which  solidifies  to  prismatic  crystals  melting  at  67°— 68°, 
soluble  with  some  dissociation  in  ten  parts  of  cold  water,  and  giving 
the  reactions  of  chloral-antipyrine. 

*  Butyl-chloral  behaves  similarly  with  antipyrine. 


BASES  FROM  TAR. 


The  numerous  constituents  of  tars  may  be  roughly  divided  into— 

(a)  Indifferent  Bodies  : — as  Hydrocarbons ; 

(b)  Acid  Bodies  : — as  Phenoloids  and  Acetic  Acid ;  and 

(c)  Bases  : — as  Ammonia,  Aniline,  Pyridine,  &c. 

The  principal  members  of  the  first  two  groups  have  already  been 
considered  at  length.  Ammonia  is  beyond  the  scope  of  present 
work,  and  the  remaining  bases  which  require  consideration  all 
belong  to  the  aromatic  group.  They  may  be  arranged  in  several 
groups,  each  one  of   which  is  represented  by  a  typical  member. 

C.NHj 
>,CH 


Thus  :— 

1.  Aniline,  or  Amido-benzene,  CgH5.NH2,  or 


H 
HC, 


CH 


CH 


2.  Kaphthylnmine,  or  Amido-naphthalene, 
CioH,.NH2,  or       .  ... 


HC 


HC 


CH        C.NHj 


c 

CH        CH 

N 


CH 


CH 


3.   Pyridine,  C5H5N,  or 


4.  Quinoline,  C9H7N,  or 


HC 

CH 

CH         N 
C. 


HC 
H 


5.  Acridine,  CigHgN,  or 


HC 


HC 


C 
CH   CH 
CH   N    CH 


CH   CH   CH 


CH 


CH 


CH 


CH 


CH 


40  ANILINE. 

From  these  formula  it  appears  that  the  substitution  of  nitrogen 
is  outside  the  ring  in  the  case  of  aniline  and  naphthylamine. 
On  the  other  hand,  pyridine,  quinoline,  and  acridine  are  derived 
from  benzene,  naphthalene,  and  anthracene  respectively,  by  the 
substitution  of  N  for  one  of  the  CH  groups  of  the  closed  chain. 

Naphthylamine  does  not  appear  actually  to  exist  in  coal-tar,  and 
aniline  occurs  in  tar  in  very  limited  quantity ;  these  bases  are 
obtained  synthetically  from  constituents  of  coal-tar. 

Besides  the  foregoing  typical  bases  and  their  allies  and  derivatives, 
certain  volatile  bases  {e.g.^  piperidine,  conine,  nicotine),  ordinarily 
prepared  from  plants,  and  therefore  classed  with  other  vegetable 
alkaloids,  have  a  connection  vrith  pyridine  or  quinoline  which  is 
now  fully  demonstrated. 


ANILINE  AND  ITS  ALLIES. 

Aniline  is  the  type  of  a  large  number  of  organic  compounds  of 
synthetical  origin. 

Aniline  has  the  constitution  of  a  mono-amidobenzene 
or  mono-phenylamine,  and  may  be  regarded  as  originating 
in  the  replacement  of  one  of  the  hydrogen  atoms  of  the  benzene- 
ring  by  the  group  amidogen,  NHg ;  or  one  of  the  hydrogen 
atoms  of  ammonia  by  the  radical  phenyl,  CgHg.     Thus : — 

C,H,.NH,,  or  (CeH,) 


H     VN 
H    j 


Aniline  exists  in  minute  quantity  in  coal-tar,  but  is  ordinarily  pro- 
duced by  nitrofying  benzene,  CgHg,  and  reducing  the  resultant 
nitrobenzene,  CgHgNOg,  by  nascent  hydrogen. 

If  the  treatment  with  nitric  acid  be  carried  further,  d  i  n  i  t  r  o- 
benzene,  CpH4(N02)2,  is  produced,  and  this  by  reduction  is 
converted  into  meta-phenylene-diamine  or  meta- 
diamido-benzene,  CgH4(NH2)2. 

If  the  reduction  of  nitrobenzene  be  effected  by  alkaline  reagents, 
two  molecules  coalesce,  and  azobenzene,  Cgfig.N  :N.CgHg,  is 
produced.  On  further  treatment  of  this  (especially  in  alcoholic  solu- 
tion) it  is  converted  into  hydrazobenzene,  CgH5.NH.NH.CgH5, 
which  by  intramolecular  change  is  transformed  into  benzidine  or 
di-para-amido-diphenyl,  NHg.CgH^.CgH^.NHg.  The  re- 
lationship of  aniline  to  the  allied  bases ^  is  shown  below; — 

*  Hydrazobenzene  has  no  basic  properties. 


BODIES   ALLIED   TO   ANILINE. 


41 


Anili}  e  (Amidobenzene). 

NH,.C6H4.H 

Phenylene-diamine. 

NH2.C6H,.NH2 

Benzidine. 

NH2.C6H,.CeH,,NH2 


Aniline. 
C6H5.NH.H 

Phenylhydrazine. 

Hydrazobenzene.  * 


Aniline  (Phenylamine). 
C6H5.NH.H 

Diphenylamine. 

CeH5.NH.CeH5 

Hydrazobenzene.  ^ 

The    true    homo- 


Aniline  forms  two  classes  of  homologues. 
1  o  g  u  e  s  (Class  A)  coexist  with  aniline  in  coal-tar,  and  are  derived 
from  aniline  by  the  substitution  of  one  or  more  methyl  groups  for 
a  corresponding  number  of  the  hydrogen  atoms  of  the  benzene 
nucleus.  They  are  ordinarily  obtained  by  nitrofying  the  corre- 
sponding hydrocarbons  prepared  from  coal-tar  naphtha,  and  reducing 
the  resultant  nitro-derivatives.  ~    Thus  : — 


Hydrocarbon. 

Benzene — 

N  itro-derivative. 

Nitrobenzene — 

Amido-derivative. 

Aniline — 

CeH^-H 

Toluene — 

Nitrotoluene — 

CeHj.NH, 

Toluidine — 

CeH,(CH3).H 
Xylene — 

CeH3(CH3),.H 

Cumene — 

CeH,(CH3),N0, 

Niti-oxylene — 
CeH3(CH3),.N02 

Nitrocumene — 

CeH,(CH3).NHj 

Xylidine — 

CeH3(CH3VNH, 
Cumidine — 

CeH,(CH3)3.H 

CeH,(CH3)3.NO, 

CeH2(CH3)3.NH2 

Isomeric  modifications  are  known  of  all  the  members  of  the  series 
except  those  in  the  first  line  (page  51  et  seq.). 

The  pseudo-homologues  of  aniline  (Class  B)  are  derived 
from  aniline  by  the  replacement  of  one  or  both  of  the  hydrogen 
atoms  of  the  amido-group  by  methyl  or  other  alkyl  radical.  Similar 
substitutions  can  be  effected  in  the  amido-groups  of  toluidine, 
xylidine,  &c. 

These  alkylated  anilines  (Class  B)  are  obtained  by  the  action 
of  methyl  chloride  or  other  alkyl  salt  on  aniline,  or  of  the 
corresponding  alcohol  on  the  hydrochloride  or  other  salt  of 
aniline  (see  page  73).  Paratoluidine  has  also  been  obtained  in  a 
very  interesting  manner  by  heating  the  hydrochloride  of  methyl- 
aniline^  to  350°  C.  in  a  sealed  tube,  when  change  of  position 
of  the  atoms  within  the  molecule  takes  place  thus  : — 


CH3  VN    = 


CeH/CHg) 
H 
H 

Para-toluidine, 


N 


H 

Methyl-aniline. 

^  Hydrazobenzene  has  no  basic  properties. 

^  If  the  hydriodide  of  methyl-aniline  be  similarly  treated,  ortho-  or  meta. 
toluidine  is  obtained. 


42  ANILINE  DERIVATIVES. 

By  the  same  process  methyl-toluidine  may  be  converted  inta 
xylidine,  and  this  by  consecutive  steps  into  a  pseudo-cumidine, 
isoduridine,  and  amido-pentamethylbenzene  (page  60).  By  treat- 
ing aniline  hydrochloride  with  aniline,  diphenylamine  or 
phenylaniline,  CgH5.NH(CgH5),  is  obtained^  (p^ge  79). 

Substitution  of  the  hydrogen  atoms  of  aniline  and  its  homologues 
can  also  be  effected  by  acid  or  chlorous  groups,  both  in  the 
benzene-nucleus  and  in  the  amido-group.  In  the  latter  case  the 
derivatives  are  called  a  n  i  1  i  d  e  s  (page  67),  and  are  quite  different 
from  the  bodies  resulting  from  the  substitution  of  chlorous 
radicals  for  the  benzenic  hydrogen.  In  the  compounds  of  the 
latter  class,  the  basic  character  is  either  much  weakened  or  entirely 
destroyed.  Most  of  the  derivatives  exist  in  several  isomeric  modi- 
fications, according  to  the  position  of  the  substituting  radicals  in  the 
benzene-nucleus.     Examples  of  the  bodies  of  this  class  are  : — 

Aniline-sulphonic    acid   or    sulphanilic  acid,   CgH4(S03lI).NH2 

(page  49). 
Nitraniline,  C6H4(X02).NH2  (page  50). 
Bromaniline,  CgH^Br.NHg. 
Trichloraniline,  CgHgClg-NHg. 

Mixed  substitution-products,  belonging  at  once  to  two  or  more 
of  the  foregoing  classes,  are  obtainable  by  suitable  means.  As 
examples  may  be  mentioned  : — 

Paranitracetanilide, C6H4(N02).NH(C2H30) 

Paranitroso-dimethylaniline,    .  CgH4(NO).N(CH3)2 

Paranitroso-dimethyl-paratoluidine,  CgH3(CH3)(NO).N(CH3)2 

The  more  important  of  the  allies  and  derivatives  of  aniline 
formulated  on  this  and  the  preceding  pages  are  described  in 
greater  detail  in  the  sequel. 

On  treating  aniline,  and  also  many  of  the  above-mentioned 
homologues  and  derivatives,  with  oxidising  agents,  a  series  of 
brilliant  colouring  matters  are  obtained,  which  form  the  well- 
known  "aniline  dyes"  (Part  I.  page  214  e^  seg-.). 

By  the  action  of  nitrous  acid,  or  a  nitrite,  on  a  cold  solution 
of  a  salt  of  aniline  a  salt  of  diazobenzeneis  obtained.  This 
and  the  allied  products  obtained  by  similar  means  from  the 
homologues  and  analogues  of  aniline  form  the  starting-point  of 
the  numerous  and  important  colouring  matters  known  as  the 
"  a  z  o-d  y  e  s  "  (Part  I.  page  175  et  seq.). 

'  Diphenylamine  and  anUine  hydrochloride  cannot  be  caused  to  react  with 
formation  of  triphenylamine,  (C6H5)3N  ;  but  this  body  can  be  obtained 
by  the  action  of  mono-brombenzene  on  di-potassium  aniline : — 
2C6H5Br  +  CeHg.  NKg = {C,U,)slS  +  2KBr. 


ANILINE.  45 

By  the  action  of  reducing  agents  on  the  salts  of  diazobenzene, 
phenylhydrazine,  C(5HgNH(NH2),  is  obtained.  The  body 
has  already  been  fully  described  (page  27). 

Aniline.'^     Amidobenzene.     Phenylamine. 
CeH,N  =  C,H,.NH, 


=      H  VN 
H  j 


Aniline  occurs  to  a  limited  extent  ready-formed  in  the  products 
of  the  distillation  of  coal,  bone,  and  peat.  Of  late  years  a  small 
quantity  has  been  actually  recovered  from  coal-tar  naphtha,  but 
almost  the  whole  of  it  is  obtained  indirectly  from  coal-tar  by 
the  action  of  a  reducing  agent  on  nitrobenzene  ("  Aniline  Oils," 
page  60).  Aniline  may  also  be  obtained  by  passing  ammonia  and 
benzene  vapour  through  a  red-hot  tube  : — CgHg  -|-  ISTHg  =  Hg  + 
CgHYN.  It  is  also  formed  together  with  diphenylamine  by 
the  reaction  of  phenol  and  ammonia.  The  best  yield  is  obtained 
by  heating  phenol  to  about  330°  for  twenty  hours  with  ammonium 
chloride  and  magnesia  or  oxide  of  zinc  (or  ammonio-zinc  chloride, 
Zn(NH3)2Cl2).  Aniline  is  also  obtained  by  numerous  other 
reactions. 

Aniline  may  be  purified  by  fractional  distillation  and  conversion 
into  the  acetyl-derivative.  This  is  recrystallised  from  water, 
and  on  saponification  yields  pure  aniline. 

Pure  aniline  is  a  colourless,  oily  liquid,  of  faintly  vinous  odour 
and  aromatic,  burning  taste.  It  refracts  light  strongly,  but  has  no 
rotatory  action.  Aniline,  when  very  pure,  freezes  at  8°  C,  but  a 
slight  admixture  greatly  reduces  its  solidifying  point.  It  boils  at 
183°-184°  C,  and  distils  unchanged. 

The  specific  gravity  of  aniline  is  1*0379  at  0°  and  1*0216  at 
20°,  compared  with  water  at  4°;  and  1*0242  at  15°,  compared 
with  water  at  the  same  temperature.  The  coefficient  of  expansion 
is  -000818. 

Aniline  becomes  yellow  or  brown  on  exposure  to  air  and  light, 
especially  at  elevated   temperatures,   a  resinous  body  being  ulti- 

1  Aniline  was  first  obtained  in  1826  byUnverdorbenby  the  dry  distilla- 
tion of  indigo,  and  received  the  naime  crystalline.  Runge  in  1834  obtained 
it  from  coal-tar,  and  termed  it  kyanol.  The  name  aniline  is  due  to  Fritsche, 
who  in  1841  obtained  it  by  distilling  indigo  with  caustic  alkali.  The  name 
benzidam  was  given  it  in  1842  by  Zinin,  who  prepared  it  by  reducing 
nitrobenzene  bj'  sulphuretted  hydrogen.  The  Tia,rrie  phenamide  h.a.s  also  been 
proposed  for  it.  Aniline  was  first  accurately  described  in  1843  by  A.  "W. 
Hofmann. 


44  CHARACTERS  OF  ANILINE. 

mately  formed.  The  change  is  due  to  oxidation,  and  does  not 
occur  in  vacuo  or  in  the  dark.^ 

Aniline  is  only  slightly  soluble  in  water,  requiring  31  parts  at 
the  ordinary  temperature,  but  being  more  soluble  in  hot  water. 
Water  also  dissolves  in  aniline,  5  parts  being  taken  up  by  100  of 
aniline  at  the  ordinary  temperature,  and  somewhat  more  at  higher 
temperatures.  The  greater  part  can  be  separated  by  distillation, 
the  water  passing  over  first,  but  the  last  traces  can  only  be  removed 
by  prolonged  digestion  over  caustic  alkali. 

Aniline  is  soluble  in  all  proportions  in  a  50  per  cent,  aqueous 
solution  of  its  hydrochloride,  and  in  smaller  proportions  in  more 
dilute  solutions  (see  page  67). 

Aniline  dissolves  readily  in  alcohol,  ether,  wood-spirit,  acetone, 
chloroform,  carbon  disulphide,  and  volatile  hydrocarbons. 

Aniline  is  itself  a  solvent  for  sulphur,  phosphorus,  indigotin, 
camphor  and  colophony,  but  does  not  dissolve  caoutchouc  or  copal. 
It  is  employed  sometimes  as  a  solvent  for  aniline-blue. 

Aniline  is  a  powerful  poison,  coagulating  albumin  and  producing 
symptoms  similar  to  those  caused  by  nitrobenzene  (Vol.  II.  page 
478).2 

Aniline  has  marked  basic  properties,  a  long  series  of  well-defined 
and  crystallisable  salts  being  obtained  from  it.  It  has,  however, 
no  action  on  phenol-phthalein,  litmus  or  turmeric,  though  it  affects 
a  few  of  the  more  delicate  vegetable  colours.  It  expels  ammonia 
from  its  salts  at  a  boiling  temperature,  but  is  itself  displaced  in  the 
cold.  Aniline  decomposes  the  solutions  of  many  metallic  salts, 
with  precipitation  of  the  corresponding  hydroxides.  When  heated 
with  strong  sulphuric  acid, aniline  is  converted  into  para-amido- 
benzene-sulphonic  acid  (sulphanilic  acid).  With  hot 
fuming  sulphuric  acid,  adi-sulphonic  acid  is  produced. 

^  According  to  A.  Bidet  {Compt.  Rend.,  cviii.  520;  Jour.  Soc.  Chem.  Ind., 
viii.  383),  aniline  and  toluidine  prepared  by  the  reduction  of  pure  nitre- 
derivatives  are  colourless  after  distillation,  and  though  they  become  yellowish 
in  a  few  days,  light  has  no  further  effect  on  them,  and  even  this  change  Bidet 
attributes  to  the  presence  ofamido-thiophene,  C4H3S. N Hg. 

2  According  to  Letheby  and  Turnbull  the  action  of  aniline  is  chiefly 
on  the  nervous  system.  According  to  Grandhomme,  the  first  symptom  in 
slight  cases  of  poisoning  by  aniline,  caused  by  inhaling  the  vapour,  is  a  blue 
colour  on  the  edge  of  the  lips,  while  the  gait  becomes  unsteady,  the  speech 
thick,  the  head  affected,  and  the  face  pale,  while  the  appetite  fails  completely. 
Alcohol  aggravates  the  symptoms.  In  more  severe  cases,  such  as  may  arise 
from  the  saturation  of  the  clothes  with  aniline,  the  lips  become  dark  blue  or 
black,  and  the  vertigo  is  so  violent  that  standing  becomes  impossible.  Accord- 
ing to  W  o  h  1  e  r  and  F  r  e  r  i  c  h  s,  aniline  does  not  exert  any  poisonous  action 
on  dogs.  R  u  n  g  e  found  the  aqueous  solution  to  kill  leeches  and  the  parts  of 
{)lants  immersed  in  it. 


REACTIONS  OF   ANILINE.  45 

In  presence  of  an  excess  of  acid,  aniline  imparts  a  deep  yellow 
colour  to  pine-wood  and  alder-pith. 

According  to  F  r  i  s  w  e  1 1,  on  adding  cupric  sulphate  to  an 
aqueous  solution  of  aniline  an  apple-green  crystalline  precipitate  is 
formed ;  or  in  extremely  diluted  solutions  a  green  coloration. 

Cold  aqueous  solutions  of  aniline  salts  are  converted  by  treat- 
ment with  nitrous  acid  (or  a  nitrite  and  mineral  acid)  into  salts  of 
diazobenzene.  On  boiling  the  solution  phenol  is  formed, 
with  evolution  of  nitrogen. 

Under  the  influence  of  oxidising  agents  aniline  gives 
products  and  reactions  which  vary  considerably  according  to  the 
oxidiser  employed,  thus  : — 

a.  When  aniline  is  treated  with  excess  of  nitric  acid,  and  the 
mixture  evaporated  at  100°  C,  the  base  is  decomposed  with  forma- 
tion of  a  brown  substance.  With  smaller  proportions  of  nitric  acid 
various  coloured  products  are  formed,  including  picric  acid. 

b.  When  treated  with  dilute  sulphuric  acid  and  manganese 
dioxide,  aniline  yields  ammonia  and  q  u  i  n  o  n  e,  CgH^Og,  but  the 
greater  part  of  the  product  undergoes  still  further  change. 

c.  If  aniline  be  dissolved  in  strong  sulphuric  acid,  and  a  few 
drops  of  a  solution  of  potassium  bichromate  be  added,  a  red  colour 
is  produced,  which  rapidly  changes  to  deep  blue. 

d.  On  treating  aniline,  or  one  of  its  salts  in  a  solid  state,  with 
strong  sulphuric  acid,  and  then  adding  a  minute  fragment  of  man- 
ganese dioxide  or  other  oxidising  agent  (in  the  manner  described 
under  "strychnine"),  a  fine  purple  coloration  is  produced. 
A  better  result  is  obtainable  by  employing  electrolytic  oxygen  ;  in 
this  form  the  test  is  the  most  delicate  and  satisfactory  which  can 
be  applied. 

e.  Chlorine  acts  on  dry  aniline  with  great  violence,  producing  a 
black  mass  containing  trichloraniline,  CgH^ClgN.  Bromine 
behaves  similarly ;  and,  on  adding  bromine-water  to  the  aqueous 
solution  of  an  aniline  salt,  a  precipitate  of  tribromaniline  is 
formed.  On  the  other  hand,  Mills  and  Muter  (Jour.  Soc.  Chem. 
Ind.,  iv.  96)  state  that  aniline  in  solution  in  carbon  disulphide 
reacts  with  Brg,  probably  forming  an  additive  compound. 

/.  When  a  solution  of  aniline  is  treated  with  a  dilute  solution  of 
bleaching  powder,  avoiding  excess,  a  fine  purple  coloration  results, 
which  gradually  changes  to  brown.  When  carefully  applied,  the 
reaction  is  delicate  and  characteristic.  The  colour  is  destroyed  by 
ether. 

g.  If  a  minute  quantity  of  aniline  be  treated  with  an  aqueous 
solution  of  phenol,  and  a  solution  of  bleaching  powder  be  then 
gradually  added,  the  reagent  produces  yellow  striae,  which  change 


46  DETECTION   OF  ANILINE. 

to  a  greenish-blue.  The  test,  which  is  due  to  J  a  c  q  u  e  m  i  n,  is 
said  to  be  very  delicate. 

h.  If  aniline,  or  one  of  its  salts  in  the  solid  state,  be  treated 
with  a  drop  of  chloroform,  and  then  solid  potash  or  a  strong 
solution  of  potash  in  alcohol  be  added,  and  the  whole  gently 
heated  by  immersing  the  tube  in  hot  water,  a  peculiar  and 
highly  unpleasant  odour  will  be  produced,  due  to  the  formation 
of  phenyl-carbamine,  CgHg.NC.  The  reaction,  which  is 
known  as  "  Hofmann's  isonitrile  test,"  is  produced  by  other 
aromatic  monamines,  and  by  acetanilide. 

Detection  and  Separation  op  Aniline. 

The  foregoing  colour-reactions  are  amply  sufficient  for  the 
recognition  of  aniline,  provided  that  a  proper  process  of 
separation  be  previously  applied. 

Aniline  may  be  liberated  from  the  aqueous  solutions  of  its 
salts  by  addition  of  caustic  soda,  and  may  then  be  extracted 
by  agitating  the  liquid  with  ether.  On  separating  the  ethereal 
layer,  and  agitating  it  with  dilute  hydrochloric  acid,  the  aniline 
passes  into  the  aqueous  liquid,  which  may  then  be  concentrated 
or  evaporated  to  dryness,  and  examined  by  the  colour-reactions 
already  described.  From  strychnine,  which  is  the  only  substance 
with  which  aniline  is  at  all  apt  to  be  confounded,  it  may  be 
separated  by  adding  caustic  soda  to  the  concentrated  solution, 
and  distilling  over  the  aniline  by  driving  in  a  current  of  steam. 
The  strychnine  remains  in  the  flask,  while  the  aniline  will  be 
found  in  the  distillate  if  it  be  acidulated  with  hydrochloric 
acid  and  concentrated  to  a  small  bulk  at  100°  C.  The  same 
plan  may  be  employed  for  detecting  aniline  in  toxicological 
inquiries,  or  the  process  used  for  isolating  strychnine  may  be 
used,  but  instead  of  evaporating  the  ether-chloroform  it  should 
be  separated  and  agitated  with  dilute  hydrochloric  acid  in  the 
manner  above  described. 

F.  Miiller  {Jour.  Chem.  Soc,  Hi.  514)  found  unchanged 
aniline  in  the  urine  of  a  person  poisoned  with  it.  The  urine 
was  optically  inactive,  but  reduced  Fehling's  solution.  A  portion 
of  the  concentrated  urine,  when  boiled  with  strong  hydrochloric 
acid,  neutralised  with  soda,  and  extracted  with  ether,  gave  an 
ethereal  solution  which  showed  the  blue  indophenol  reaction. 
The  ethereal  extract  of  the  unboiled  urine  did  not  give  this 
reaction,  a  fact  which  Miiller  believes  was  due  to  the  secretion 
of  the  aniline  as  para-amidophenylsulphate  (compare  "  Phenyl- 
Sulphuric  Acid,"  Part  I.  page  9) ;  a  substance  which  is  split  up 
by  boiling  with  hydrochloric  acid.  In  support  of  this,  the 
original  urine  contained  sulphates  (estimated  by  barium  chloride) 


DETERMINATION   OF   ANILINE.  47 

equivalent  to  only  0*0475  gramme  of  sulphuric  acid  per  litre ; 
but  after  boiling  with  hydrochloric  acid,  0*8085  gramme.  A 
direct  test  for  the  presence  of  paramidophenylsulphates  in  urine 
consists  in  boiling  the  liquid  with  one-fourth  of  its  measure 
of  strong  hydrochloric  acid,  adding  a  few  c.c.  of  a  3  per  cent, 
solution  of  phenol,  and  then  some  drops  of  a  chromic  acid 
solution.  If  para-amidophenol  be  present,  the  liquid  becomes 
red,  and  turns  blue  on  adding  ammonia. 

The  determination  of  aniline  may  be  effected  by  evaporating  its 
ethereal  solution,  or  preferably  by  extracting  the  base  therefrom 
by  agitation  with  dilute  hydrochloric  acid,  evaporating  the  acid 
liquid,  and  weighing  the  residual  hydrochloride.  Under  favour- 
able circumstances  it  may  be  measured  after  liberation  from 
a  strong  solution  of  the  hydrochloride  by  addition  of  caustic 
alkali. 

instead  of  weighing  the  aniline  hydrochloride,  the  salt  may  be 
redissolved  in  water,  and  the  solution  titrated  with  standard  silver 
nitrate.  Or  it  may  be  titrated  with  standard  caustic  alkali  and 
phenolphthalein  or  litmus,  as  aniline  hydrochloride  acts  on  these 
indicators  exactly  like  an  equivalent  quantity  of  free  hydrochloric 
acid,  and  the  end-reaction  is  perfectly  sharp.  The  process  allows 
of  the  titration  of  aniline  in  presence  of  neutral  ammoniacal  salts. 
On  the  other  hand,  with  helianthin  (methyl-orange),  the  basic 
character  of  free  aniline  is  distinctly  marked,  but  the  end-reaction 
is  not  sufficiently  definite  to  render  the  indicator  available  for 
accurately  titrating  aniline. 

According  to  Julius  {Jour.  Soc.  Dyers,  ^c,  ii.  79),  free 
aniline  in  aqueous  solution  can  be  satisfactorily  titrated  with' 
standard  sulphuric  or  hydrochloric  acid,  if  congo-red  be  employed 
as  an  indicator  and  the  neutral  point  be  regarded  as  that 
at  which  a  bluish-violet  colour  is  obtained,  not  changed  by 
further  small  additions  of  acid;  but  a  much  larger  excess  is 
required  to  produce  a  pure  blue.  Results  are  said  to  be 
obtainable  agreeing  within  0"2  per  cent,  with  theory. 

Salts  of  Aniline. 

Aniline  combines  readily  with  acids  forming  a  series  of  salts 
which  crystallise  well.     The  following  are  the  most  important. 

Aniline  Hydrochloride.  Hydrochlorate  of  Aniline.  CgHyN,Hd. 
This  salt  crystallises  with  great  facility  in  colourless  needles 
or  large  plates,  which  are  very  soluble  in  water  and  alcohol. 
It  melts  at  192°  C,  and  may  be  sublimed  unchanged.  It 
yields  double  salts  with  stannic,  mercuric,  antimonious,  platinic 
and  auric  chlorides ;  aniline  chloroplatinatej  {C^^l^,T{.C\)^tGl^y 
crystallises  from  hot    water  in    yellow  needles.     Aniline  salt  is 


48  ANILINE  SALT. 

the  ordinary  commercial  name  for  aniline  hydrochloride.  It  is 
manufactured  by  mixing  the  calculated  weights  of  aniline  and 
hydrochloric  acid  in  stone-tanks,  freeing  the  crystals  formed 
from  the  mother-liquor  by  a  centrifugal  machine,  and  drying 
them.  According  to  another  process,  aniline  is  dissolved  in 
petroleum  spirit  of  0"720  specific  gravity,  and  hydrochloric  acid 
gas  passed  in  till  the  solution  is  saturated.  The  aniline  salt  is 
deposited  as  a  white  powder,  which  is  separated  from  the 
adhering  petroleum  spirit  by  hydraulic  pressure,  and  ground  to 
powder. 

Aniline  salt  is  employed  largely  in  calico-printing,  its  chief 
use  being  for  the  production  of  aniline-hlack  (Part  I.  page  250). 
It  is  important  that  the  salt  intended  for  this  purpose  should  be 
made  from  pure  aniline,  and  should  be  dry  and  neutral.  The 
presence  of  free  acid  in  the  aniline  salts  is  liable  to  cause  the 
cloth  dyed  black  to  rot  in  the  steaming  process.  It  must  be 
free  from  sand  or  grit,  which  would  injure  the  printing 
rollers,  and  will  produce  streaks  on  the  printed  cloth.  GhHt 
remains  undissolved  when  the  sample  is  treated  with  hot  water, 
and  may  be  filtered  off,  dried  or  ignited,  and  weighed.  Free 
acid  is  best  determined  by  titration  with  decinormal  caustic 
alkali,  using  methyl-orange  as  an  indicator,  but  the  results  are 
not  very  satisfactory.  A  useful  method  of  examination  consists 
in  titrating  the  aqueous  solution  of  2  grammes  of  the  sample 
with  normal  caustic  soda,  using  litmus  or  phenolphthalein  a& 
an  indicator.  The  amount  neutralised  corresponds  to  the  total 
acid,  both  free  and  combined  with  aniline.  Theoretically,  2 
grammes  of  pure  aniline  hydrochloride  would  require  15*4  c.c. 
of  normal  caustic  soda,  but  owing  to  the  presence  of  toluidine 
and  moisture  commercial  samples  of  good  quality  require  between 
14  and  15  c.c.^  The  process  will  indicate  the  presence  of 
ammonium  chloride,  which  will  not  neutralise  alkali,  and  hence 
a  sample  containing  it  will  require  a  less  volume  of  the 
standard  solution.  Ammonium  chloride  is  occasionally  met 
with  in  considerable  proportion  as  an  adulterant  of  aniline  salts. 
For  its  accurate  determination  the  sample  should  be  dissolved  in 
water,  excess  of  caustic  soda  added,  the  liberated  aniline  separated, 
and  the  aqueous  solution  distilled  in  the  usual  way.  On  titrating 
the  distillate  with  standard  acid  and  litmus  or  phenolphthalein,  only 
the  ammonia  will  be  indicated.  Fixed  impurities  will  be  detected 
on  igniting  the  sample ;  a  mere  trace  should  be  present.     An  idea 

^  This  method  of  examining  aniline  salts  is  due  toR.  "Williams  {Chem. 
News,  1.  299),  but  he  appears  to  attribute  the  reaction  to  the  presence  of 
free  acid. 


ANILINE-SULPHONIC   ACIDS.  49 

of  the  proportion  of  tohddine  present  in  the  sample  can  be  obtained 
by  liberating  the  mixed  bases  from  the  solution  of  the  salts  by 
caustic  soda,  and  heating  a  few  centimetres  of  the  aniline  with  an 
equal  quantity  of  strong  arsenic  acid  solution  to  180°  C.  for  some 
time.  On  boiling  the  product  with  water,  the  intensity  of  the 
crimson  coloration  will  increase  with  the  proportion  of  toluidine 
in  the  sample.  A  more  accurate  result  can  be  obtained  in  the 
manner  indicated  on  page  64. 

Aniline  Sulphate,  (CgH7N)2H2S04.  This  salt  forms  a  crystal- 
line powder,  which  is  readily  soluble  in  water  and  slightly  so  in 
alcohol.  It  is  insoluble  in  ether,  a  fact  which  distinguishes  it  from 
the  sulphate  of  methylamine. 

Aniline  Oxalate,  (CgH7]Sr).,H2C204,  is  very  slightly  soluble  in 
cold  water  or  alcohol,  and  insoluble  in  ether. 

Aniline  Acetate,  CgH7N,HC2H302,  does  not  appear  to  have  been 
obtained  in  a  crystalline  form.  When  heated  it  loses  the  elements 
of  water  and  forms  acetanilide  (see  page  68). 

Aniline-sulphonic  Acids.  Amidobenzene-sulphonic  Acids. 
When  aniline  is  treated  with  an  equivalent  amount  of  dilute  or 
concentrated  sulphuric  acid  it  is  converted  into  aniline  sulphate 
If  an  excess  of  acid  be  used,  a  high  temperature  employed,  or  sul- 
phuric anhydride  be  present,  aniline-sulphonic  acid  is  produced: — 

CeH,.NH,  +  SO,(OH),  =  C,H,  {  ^^'^^  +  H.OH 

Three  modifications  of  this  body  exist,  which  differ  according  to 
the  relative  positions  of  the  NHg  and  SO3H  groups  in  the  benzene- 
chain.  The  ortho-sulphonic  acid  (1:2)  has  no  practical 
interest,  but  the  m  e  t  a-  and  par  a-acids  are  manufactured  on  a 
large  scale  for  the  production  of  aniline-  and  azo-dyes. 

Meta-amidohenzenesulphonic  Acid,  CgH^(NH2)^^>.S03lI(^),  is  em- 
ployed for  the  manufacture  of  metanile-yelluio  (Part  I.  page  190). 
It  is  prepared  by  warming  nitrobenzene  with  fuming  sulphuric 
acid,  or  by  treating  a  solution  of  benzene  in  strong  sulphuric  acid 
with  fuming  nitric  acid,  when  a  mixture  of  nitro-benzenesul- 
phonic  acids,  CgH^(N02)S03H,  is  obtained,  in  which  the 
meta-acid  predominates,  and  may  be  roughly  separated  from  its 
isomers  by  conversion  into  the  barium  or  calcium  salt.  The  meta- 
nitro-sulphonic  acid  yields,  on  reduction,  the  corresponding  amido- 
sulphonic  acid. 

Para-amidobenzenesulphonic  Acid,  CgH4(NH2)(^).S03HW,  likewise 
called  Sulplianilic  Acid,  is  prepared  on  a  large  scale  by  heating 
one  part  of  aniline  and  three  of  concentrated  sulphuric  acid  to 
195°.    With  fuming  acid,  the  reaction  occurs  more  rapidly  and  at  a 

VOL.  III.  PART  II.  D 


50 


NITRANILINES. 


lower  temperature.  On  pouring  the  cooled  product  into  water,  the 
acid  separates  as  a  crystalline  mass,  which  can  be  recrystallised 
from  hot  water. 

Sulphanilic  acid  crystallises  in  rhombic  tables  containing  1  aqua, 
which  effloresce  in  the  air,  and  are  only  slightly  soluble  in  cold, 
but  readily  in  hot,  water,  Treatment  with  potassium  bichromate 
and  sulphuric  acid  oxidises  it  to  q  u  i  n  o  n  e,  CgH^Og.  The  solution 
of  the  sodium  salt,  on  treatment  with  sodium  nitrite,  yields  sodium 
diazobenzenesulphonate  (Part  I.  page  177).  Aniline 
sulphanilate  gives  off  all  its  base  at  100°. 

NiTRANiLiNES.  When  aniline  is  treated  with  dilute  nitric  acid 
it  yields  aniline  nitrate.  With  the  concentrated  acid  it  reacts  far 
more  violently  than  benzene,  and  is  converted  into  q  u  i  n  o  n  e 
and  other  products.  To  obtain  a  nitro-derivative  by  such  means, 
the  aniline  must  be  protected  by  employing  its  acetyl-derivative, 
or  by  nitrofying  in  presence  of  excess  of  strong  sulphuric  acid.  In 
the  latter  case  a  mixture  of  the  three  isomeric  nitranilines  is 
obtained,  but  chiefly  the  me^a-compound ;  in  the  former  case  pai^a- 
nitracetanilide,  CgH4(N02).NH(C2H30),  is  formed,  together 
with  some  of  the  07'^^o-compound,  both  of  which  readily  yield  the 
corresponding  nit r aniline,  CgH4(N02).NH2,  on  boiling  with 
concentrated  hydrochloric  acid  or  caustic  alkali. 

Another  method  of  preparing  the  nitranilines,  especially  the  meta- 
modifi cation,  is  the  reduction  of  the  corresponding  dinitrobenzenes 
in  alkaline  alcoholic  solution.  Under  these  circumstances  only 
one  of  the  NOg  groups  is  reduced  to  NHg,  whereas  in  acid  solu- 
tions diamidobenzene,  CgH^  : (NH2)2,  is  obtained  (page  86). 


Nitranilines,  C6H4(N02).NH2  . 

Ortho. 

Meta. 

Para. 

Appearance  and    \ 
Crystalline  form,) 

N02:NH2=1:2 

N02:NH2=l:3 

N02:NH2=1:4 

Orange-yellow 
needles. 

Long  yellow  needles. 

Long  yellow  needles. 

Taste 

... 

Sweet,  burning. 

Nearly  tasteless. 

Melting-point,    .     . 

71' 

114° 

147° 

VolatUity,      .     .     . 

Distils  in  a  current 
of  steam. 

Sublimes     at    100°. 
Distils  in  a  cur- 
rent of  steam. 

Not    volatile    with 
steam. 

Salts 

Very  unstable. 

Fairly  stable. 

Unstable. 

Behaviour       when 
boiled  with  strong 
soda, 

••• 

Unchanged. 

Forms     para-nitro- 
phenol— 

C6H4(N0.,).0H 

The  nitranilines  are  yellow  crystalline  bodies,  readily  soluble  in 
alcohol  but  only  slightly  so  in  water.     They  are  weak  bases  form- 


HOMOLOGUES  OF   ANILINE.  51 

ing  yellow  salts,  and  yield  the  corresponding  diamidobenzenes  on 
reduction.     The  preceding  table  exhibits  their  chief  differences. 

Two  dimtramUnes,  CgH3(]S'02)2.NH2,  are  known,  melting  re- 
spectively at  1 82°  or  1 38°.  Also  a  tnnitranUine,  C^j^^0^^.^n^ 
or  picramide,  which  melts  at  186°,  and  is  converted  into 
picric  acid,  05112(^02)3.011,  and  ammonia  when  boiled  with 
caustic  alkali. 

Homologues  of  Aniline. 

As  already  stated,  the  true  homologues  of  aniline  are  bodies  in 
which  one  or  more  atoms  of  the  hydrogen  of  the  benzene-nucleus 
are  replaced  by  a  corresponding  number  of  atoms  of  methyl  or 
other  alkyl  radical.  The  compounds  in  question  may  be  prepared, 
and  are  produced  commercially,  by  processes  exactly  similar  to 
those  which  result  in  the  formation  of  aniline.  That  is,  the  hydro- 
carbons toluene,  xylene,  &c.,  are  treated  with  nitric  acid,  and  the 
resultant  nitro-derivatives  are  reduced  to  the  bases  by  nascent 
hydrogen  (usually  iron  and  hydrochloric  acid). 

In  their  general  chemical  relationships  the  homologues  present 
the  closest  resemblance  to  aniline,  and  yield  substitution-products 
of  a  strictly  parallel  character.     They  are  also  diazotised  similarly. 

The  only  homologues  of  aniline  which  require  separate  descrip- 
tion are  the  toluidines,  C^HgN,  and  the  xylidines,  CgHj^^N. 
Their  consideration  will  be  followed  by  a  section  describing 
"  aniline  oils,"  under  which  term  is  included  commercially  pure 
aniline  and  toluidine,  and  various  mixtures  of  these  bases. 

Toluidines.  Amidotoluenes.  Amido-methylbenzenes.  Tolyl- 
amines. 

C7H9N  =  C7H7.NH2  =  C6H,(CH3) 


'H3)) 
H     VN 

H    j 


The  toluidines  exist  in  small  quantity  together  with  aniline  in 
coal-tar.  They  are  produced  commercially  from  toluene  by  processes 
exactly  analogous  to  those  by  which  aniline  is  prepared  from  ben- 
zene, and  together  with  aniline  constitute  nearly  the  whole  of  the 
"  aniline  oils  "  of  commerce  (page  60).  An  interesting  method  of 
producing  toluidine  is  mentioned  on  page  41. 

Three  isomeric  modifications  of  toluidine  are  known.  The  chief 
physical  differences  between  them  are  shown  in  the  following  table, 
in  which  they  are  also  contrasted  with  aniline  and  their  meta- 
meride  benzylamine,  CgHg.CHgNHg.^ 

'^  Benzylamine  is  a  colourless  liquid  of  faint  aromatic  odour,  and  is  not 
affected  by  light.     It  is  miscible  in  all  proportions  with  water,  alcohol  and 


52 


ISOMERIC   TOLUIDINES. 


Aniline. 

Ortho- 

toluidine. 

CH3:NH2  =  1:2 

Meta- 

toluidine. 

CH3:NH2  =  1:3 

Para- 

toluidine. 

CH3:NH2  =  1:4 

Bemylamine. 

Specific  gravity  at 
15°, 

1-0268 

1-0037 

0-998  (at  25°) 

Solid. 

-990 

Melting-point,      . 

Solidifies  at 

-8°0. 

Does  not  soli- 
dify at -20° 

Does  not  soli- 
dify at -13° 

Melts  at -1-45° 

Liquid. 

Boiling-point, 

183°-7 

199° 

197° 

198° 

185° 

Characters  of 
the  acetyl-deriva- 
tive  :— 

Melting-point, 

114* 

107' 

65°-66° 

147° 

57'-61' 

Boiling-point, 

295° 

296° 

302°-304° 

307° 

300° 

1000    parts    of 
water  dissolve, 

3-4  at  14° 

8-6  parts  at  19° 

4-4  parts  at  13° 

0-89  at  22° 

Soluble. 

Solubility   of   the 
acid  oxalate  :— 

In  1000  parts  of 
water  at  15°, 

.. 

28-8 

26-5 

8-7 

In  1000  parts  of 
ether  at  15°, 

... 

0-50 

Very  slight. 

0-016 

... 

Ortho- toluidine  is  formed  by  the  reduction  of  ortho-nitro- 
toluene.  It  is  a  colourless  liquid,  turning  brown  on  exposure 
to  air  or  light,  and  otherwise  closely  resembling  aniline.  It 
•differs  from  its  isomerides  by  giving  a  green  coloration  when 
treated  with  ferric  chloride  and  a  little  para-diamidobenzene. 
A  solution  of  1  in  10,000  gives  a  fairly  deep  coloration,  and 
one  of  1  in  100,000  assumes  a  distinct  greenish  tint.  All 
commercial  aniline  gives  this  reaction,  and  even  that  prepared 
by  the  distillation  of  indigo  with  caustic  alkali. 

Meta-toluidine  is  produced  by  the  reduction  of  meta-nitrotoluene, 
preferably  by  an  acid  solution  of  stannous  chloride.  It  is  only 
present  in  small  proportion  in  commercial  toluidine.  For  its 
detection  and  approximate  determination  the  mixed  bases  are 
■converted  into  hydrochlorides,  and  the  greater  part  of  the 
isomeric  salts  removed  by  fractional  crystallisation.  The  mother- 
liquor  is  evaporated  to  dryness,  and  the  residue  heated  with 
methyl  alcohol  to  200°,  under  pressure,  for  a  considerable  time. 
This  produces  a  mixture  of  the  three  isomeric  dimethyl-toluidines. 


•ether,  but  is  separated  from  its  aqueous  solutions  by  caustic  alkalies  (con^pare 
"Pyridine  ").  It  lias  a  strongly  alkaline  reaction,  fumes  with  hydrochloric  acid, 
and  absorbs  carbon  dioxide  from  the  air,  with  conversion  into  silky  needles  of 
the  carbonate. 


DISTINCTION   OF  TOLUIDINES. 


53 


but  only  the  meta-modification  yields  a  nitroso-derivative, 
CgH3(NO)(CH3).N(CH3)2,  on  adding  sodium  nitrite  to  an  ice-cold 
solution  of  its  hydrochloride.  The  hydrochloride  of  nitroso- 
dimethylmetatoluidine  thus  prepared,  crystallises  from  a 
hot  acidulated  solution  in  greenish-yellow  needles  only  slightly 
soluble  in  cold  water.  On  treatment  with  sodium  carbonate 
the  free  base  is  obtained,  melting  at  92°,  crystallising  from  water 
or  ether  in  small  green  plates  or  long  needles,  and  precipitated 
in  moss-green  needles  on  adding  petroleum  ether  to  its  chloro- 
formic  solution.  All  its  solutions  have  a  deep  green  colour. 
Nitroso-dimethylmetatoluidine  forms  steel-blue  compounds  with 
aniline  and  orthotoluidine. 

According    to    Rosenstiehl,    the    three    modifications    of 
toluidine  may  be  distinguished  by  the  following  reactions : — 


Orthotoluidine. 

Metatoluidine. 

Paratoluidine. 

1.  To  a  solution  of  the 

Blue        coloration 

Yellow-brown 

Yellow  coloration. 

base    in    sulphuric 

changing          on 

coloration,      be- 

acid,   of    1-75    sp. 

dilution      to      a 

coming  greenish- 

gr.,  add  a  solution 

permanent     red- 

yellow  on  slight 

of  chromic  acid  in 

violet. 

dilution,         and 

sulphuric    acid    of 

colourless        on 

the  same  strength. 

further   addition 
of  water. 

2.  To   a   solution    of 

Orange  coloration, 

At  first  red,  rapidly 

Blue  streaks  which 

the    base     in    sul- 

or  in   very  con- 

changing  to    in- 

soon   tinge    the 

phuric  acid  of  1-75 

centrated     solu- 

tense   blood-red. 

whole  liquid ;  (in 

sp.  gr.,  add  nitric 

tions,  brown,  be- 

and   then    dirty 

presence  of   ani- 

acid. 

coming  yellow  on 

red ;  on  dilution, 

line     or     ortho- 

dilution. 

orange. 

toluidine,    blood 
red).    The  colour 
quickly  becomes 
violet,  then  red, 
and,  after  some 
hours,  brown. 

8.  Dissolve   the  base 

The  aqueous  layer 

The  aqueous  layer 

No   reaction.      In 

in  ether,   and   add 

becomes  first  yel- 

becomes a  thick 

presence  of  ani- 

an equal  volume  of 

low     and     then 

brownish-yellow. 

line     the    ether 

water.     Then    add 

brown.           The 

The         ethereal 

becomes  blue  on 

a  few  drops  of  clear 

ethereal      layer. 

layer       becomes 

agitation. 

solution  of  bleach- 

after separation. 

reddish,          and 

ing  powder. 

gives       a      per- 

after   separation 

manent  reddish- 

and   addition   of 

violet  coloration 

dilute    sulphuric 

with   dilute  sul- 

acid  is  coloured 

phuric  acid. 

violet      at      the 
under-surface. 

Para-toluidine  is  produced  by  the  reduction  of  the  nitrotoluene 
derived  from  the  toluene  produced  by  the  dry  distillation  of 
Tolu  balsam ;  also  by  heating  paracresol  to  300°  with  ammonia 
and  chloride  of  zinc ;  and  by  molecular  transposition  from 
methylaniline  hydrochloride   (page  41).     It  crystallises  from  hot 


54  COMMERCIAL  TOLUIDINE. 

dilute  alcohol  in    colourless    plates   melting  at   45°,  and   has    a 
peculiar  odour  recalling  that  of  aniline. 

Commercial  Toluidine  consists  chiefly  of  a  mixture  of  the 
ortho-  and  para-  modifications.  According  to  Friswell,  the 
specific  gravity  of  the  orthotoluidine  of  commerce  should  be 
about  1-0037,  and  its  boiling-point  from  197°  to  198°  C.  It 
ought  not  to  solidify  on  cooling  to  —  4°,  though  the  majority 
of  samples  contain  sufficient  paratoluidine  to  cause  them  to 
commence  crystallising  at  this  temperature.  The  paratoluidine 
of  commerce  occurs  in  white  dry  crystals,  melts  at  43°-45°, 
and  distils  between  196°  and  198°.  Liquid  commercial  toluidine 
should  boil  at  197°-198°,  have  a  specific  gravity  of  about  1*000, 
and  contain  from  30  to  40  per  cent,  of  paratoluidine  and  60 
to  70  of  orthotoluidine. 

A  portion  of  the  para-modification  separates  from  the  com- 
mercial mixture  of  the  isomers  when  the  liquid  is  cooled  by  a 
freezing  mixture.  A  further  separation  is  effected  in  practice 
by  fractionally  saturating  the  mixture  of  the  bases  with  sulphuric 
acid,  and  then  distilling  in  a  current  of  steam.  Orthotoluidine 
being  a  weaker  base  than  the  para-compound,  the  former  will 
alone  pass  into  the  distillate  if  the  quantity  of  sulphuric  acid 
employed  be  somewhat  in  excess  of  that  requisite  to  neutralise 
the  paratoluidine. 

L.  Lewy  {Jour.  Chem.  Soc,  1.  872;  Jour.  Soc.  Chem.  Ind., 
V.  481)  has  proposed  to  separate  ortho-  and  para- toluidine  by 
converting  the  bases  into  phosphates.  It  appears  that  when  para- 
toluidine and  orthophosphoric  acid  are  brought  together,  c?2.'-toluidine 
orthophosphate,  (C7H9N)2ll3P04,  is  produced  as  a  salt  crystallising 
in  scales  and  very  sparingly  soluble  in  cold  water,  but  more  readily, 
with  partial  dissociation,  in  boiling  water.  Aniline  acts  simi- 
larly, forming  a  sparingly  soluble  di-amlmG  orthophosphate, 
(CQHyN)2H3P04.  On  the  other  hand,  orthotoluidine  forms  a 
mowo-toluidine  orthophosphate,  (C7ll9N)H3P04,  and  never  a  di- 
or  tri-  salt.  Hence  in  the  phosphates  obtained  from  a  mixture  of 
the  two  toluidines  the  proportions  of  the  bases  might  be  deduced 
from  the  percentage  of  phosphoric  acid.  The  mono-orthotoluidine 
phosphate  is  more  readily  soluble  in  water  than  dipara toluidine 
or  dianiline  phosphate.  Further,  when  its  solution  is  shaken 
with  free  aniline  or  paratoluidine,  the  orthotoluidine  is  set  free. 
Hence  pure  orthotoluidine  can  be  obtained  from  commercial 
toluidine^  by  adding  rather  more  of  a  21  per  cent,  aqueous 
solution  of  phosphoric  acid  than  will  suffice  to  form  diphosphates 

^  The  xylidines  and  cumidines  behave  like  orthotoluidine,  and  form  only 
monophosphates. 


SEPARATION   OF  TOLUIDINES.  55 

with  the  aniline  and  paratoluidine  present.  On  warming  the 
liquid,  the  free  orthotoluidine  forms  a  layer  at  the  surface,  which 
may  be  separated  and  distilled.  The  process  may  be  modified  by 
adding  a  further  quantity  of  phosphate  to  convert  the  ortho- 
toluidine into  monophosphate,  and  then  cooling  the  liquid  aiid 
allowing  it  to  stand  to  secure  the  complete  deposition  of  the 
paratoluidine  phosphate.  ■ 

Wolfing  (^e?-.,  xix.  2132)  states  that  orthotoluidine  pre- 
pared by  Lewy  himself  by  the  above  process,  both  on  the  small 
and  large  scale,  still  contained  as  much  as  4  per  cent,  of  para- 
toluidine. For  the  preparation  of  pure  paratoluidine  he  recom- 
mends (Dingl.  Polyt.  Jour.,  cclxiii.  260)  that  the  hydrochlorides 
of  the  bases  should  be  treated  with  an  amount  of  sodium 
nitrite  only  sufficient  to  convert  the  orthotoluidine  present  into 
a  m  i  d  0  a  z  0 1 0 1  u  e  n  e.  Only  when  this  change  is  complete 
does  the  paratoluidine  react  with  the  nitrite  to  form  a  diazo- 
amido-com})ound. 

A  method  of  determining  the  proportions  of  the  ortho-  and  para- 
moilifications  of  toluidine  in  the  commercial  product  has  been  based 
byRosenstiehl  on  the  different  solubilities  of  the  acid  oxal- 
ates of  the  two  bases.  The  acid  oxalate  of  paratoluidine  requires 
6660  parts  of  ether  for  solution,  while  the  corresponding  salt  of  ortho- 
toluidine dissolves  in  200  parts  of  ether.  The  method,  somewhat 
modified,  is  as  follows  : — 0'2  gramme  of  the  sample  is  dissolved  in 
80  c.c.  of  anhydrous  ether  free  from  alcohol;  1  059  gramme  of 
anhydrous  oxalic  acid,  or  1*177  gramme  of  the  crystallised,  acid  is 
dissolved  in  250  c.c.  of  anhydrous,  alcohol-free  ether.  Each  c.c. 
of  this  solution  will  precipitate  0*005  gramme  of  toluidine.  An 
excess  is  added  to  the  ethereal  solution  of  the  sample,  the  liquid 
allowed  to  stand  in  a  stoppered  bottle  for  twelve  hours,  then 
filtered  through  paper,  and  the  precipitate  washed  with  ether.  The 
precipitate  is  then  washed  into  the  bottle  with  water,  and  tho 
solution  titrated  with  decinormal  caustic  alkali  and  phenolphthalein. 
1  CO.  of  decinormal  alkali  represents  0'00535  gramme  of  para- 
toluidine. ^I  i  n  i  a  t  i.  Booth,  and  Cohen  {Jour.  Soc.  Chem. 
Ind.,  vi.  419)  find  that  if  too  long  a  time  be  allowed  for  the  pre - 
cipitatioi),  the  product  is  liable  to  contain  the  orthotoluidine 
oxalate,  and  hence  the  result  will  be  above  the  truth.  They 
recommend  that  a  repetition  of  the  experiment  should  be  made, 
in  whicli  the  amount  of  oxalic  acid  solution  used  is  only  that 
requisite  to  combine  with  the  paratoluidine  found  by  the  first 
test',  so  reducing  the  error  to  a  minimum. 

G.  Lunge   {ChemiscJie  Ind.,  viii.  74;  Jour.  Soc.  pTjers^^c^  I 
150)  estimates  the  proportion  of  para-  and  ortho-toluidine  in  a 


56 


DENSITY  OF  TOLUIDINES. 


mixture  of  the  two  by  a  careful  observation  of  the  specific  gravity. 
The  determination  is  made  by  the  bottle,  and  referred  to  water  at 
15°  C.  If  the  sample  does  not  contain  more  than  50  per  cent,  of 
paratoluidine  it  is  liquid  at  15°,  and  consequently  the  observation 
is  made  at  that  temperature.  With  50  to  60  per  cent,  of  para- 
toluidine the  method  is  still  available  if  the  bottle  be  filled  at 
20°  C. ;  but  with  still  larger  proportions  the  results  are  unreliable,  as 
the  correction  for  temperature  loses  in  accuracy,  and  the  differences 
in  specific  gravity  become  very  small  for  considerable  alterations  in 
the  composition  of  the  mixture.  It  is  very  desirable  to  adhere  rigidly 
to  the  prescribed  temperature,  as  an  error  of  1°  C.  causes  an  error 
of  7  per  cent,  in  the  estimation.  The  correction  is  zh  0'0008  for 
1°,  when  the  density  is  above  1*0008,  and  ±  0'0007  when  below 
that  point.  All  water  must  be  removed  by  treating  the  sample 
with  powdered  caustic  potash  and  redistilling.  The  distillation 
also  serves  to  show  the  presence  of  analine  or  xylidine,  in  presence 
of  notable  quantities  of  which  the  method  is  inapplicable. 

Lunge  gives  the  following  table  of  densities  of  mixtures  of 
para-  and  ortho-toluidine,  water  at  15°  being  taken  as  unity : — 


Specific 

Ortho- 

Specific 

Ortho- 

Specific 

Ortho- 

Specific 

Ortho- 

gravity  at 

toluidine. 

gravity  at 

toluidine. 

gravity  at 

toluidine. 

gravity  at 

toluidine. 

16- C. 

Per  cent. 

15- C. 

Per  cent. 

20°  C. 

Per  cent. 

20°  C. 

Per  cent. 

10037 

100 

1-0016 

82J 

0-9995 

65J 

0-9939 

50 

36 

99 

15 

82 

94 

65 

38 

49i 

35 

98 

14 

81 

93 

64 

37 

48J 

34 

97 

13 

80 

92 

63 

36 

48 

33 

96 

12 

79J 

91 

62 

35 

*7J 

32 

95 

11 

?,1 

90 

61J 

34 

46i 

81 

94 

10 

89 

61 

33 

46 

80 

93i 

09 

77 

88 

60 

32 

45 

29 

^1 

08 

76 

87 

59 

31 

44i 

28 

07 

75 

86 

-     58J 

30 

44 

27 

91 

06 

74 

85 

58 

29 

43 

26 

90 

05 

73 

84 

57i 

28 

42 

25 

89i 
88} 

04 

72i 

83 

56i 

27 

41 

24 

03 

72 

82 

56 

0-9926 

40 

23 

88 

02 

71 

81 

55 

22 

87 

01 

70 

80 

54i 

21 

86J 

1-0000 

69 

79 

54 

20 

86 

0-9999 

68J 

78 

63 

19 

85 

98 

68 

77 

52^      1 

18 

m 

97 

67 

76 

51i       1 

1.0017 

83i 

0-9996 

66J 

0-9975 

51 

A  method  of  separating  orthotoluidinefrom  paratoluidine  has  been 
based  by  P.  Schoop  (Chem.  Zeit,  ix.  1785;  Jour.  Soc.  Chem. 
Ind.y  V.  178)  on  the  observation  of  We  ith  and  Merz,  that  the 
acetyl-derivative  of  orthotoluidine  is  far  less  soluble  in  water  than 
that  of  the  isomer  and  of  aniline.  Schoop's  method  has  been  found 
unsatisfactory  by  several  chemists,  and  need  not  be  further  described. 

A  method  of  estimating  paratoluidine  in  admixture  with  ortho- 


XYLIDINES. 


57 


toluidine  has  been  based  by  G.  A.  S  c  h  o  e  n  (Chem.  Zeit,  xii.  494  ; 
Jour.  Soc.  Chem.  Ind.,  vii.  594)  on  the  intensity  of  the  red  colour 
produced  with  potassium  bichromate.  If  the  specific  gravity 
indicates  the  presence  of  more  than  8  per  cent,  of  paratokiidine  it 
is  reduced  below  that  proportion  by  adding  orthotoluidine.  1  c.c. 
of  the  oil  is  then  dissolved  in  2  c.c.  of  hydrochloric  acid  and  30  of 
water,  and  1  c.c.  of  a  cold  saturated  solution  of  bichromate  of 
potassium  added.  The  mixture  is  allowed  to  stand  for  an  hour, 
with  occasional  stirring,  and  is  then  filtered.  Orthotoluidine 
gives  a  black  lake  and  a  colourless  liquid,  but  in  presence  of  para- 
toluidine  the  precipitate  is  light  brown,  and  the  filtrate  has  a  red 
colour,  intense  in  proportion  to  the  paratoluidine  present.  Pure 
aniline  behaves  like  orthotoluidine,  but  in  presence  of  the  latter  a 
red  filtrate  is  produced.  Hence  aniline  must  be  absent,  or  its 
amount  must  be  deduced  from  the  boiling-point  and  specific  gravity 
of  the  sample,  and  a  corresponding  amount  added  to  the  standard 
mixture  with  which  the  sample  is  compared. 

Xylidines.     Amido-dimethylbenzenes.     CgH3(CH)2.NH2. 

Six  isomeric  bodies  of  the  above  formula  are  theoretically  pos- 
sible, and  all  of  them  are  known.     Thus  :^ — 


Base. 

Positions  of 

Groups. 

CH3:CH3:NH2 

Boiling- 
Point,  •  C. 

Acetyl-Derivative. 

Characters  of 
Hydrochloride. 

Melting- 
Point,  •  C. 

Appearance, 
&c. 

»-Orthoxylidine, 

o-Orthoxylidine, 
r-MetaxyUdine, 

a-MetaxyUdine, 

a-Metaxylidine, 
Paraxylidine, 

1:2:3 

1:2:4 
1:3:2 

1:3:4 

1:8:5 
1:4:2 

223 

226 

(melts  at 

49) 

214 

212 

220 
212*5 

134 

99 
176-8 

129 

140-5 
139 

White 
needles. 

Long  vitreous 
prisms. 

White 
needles ; 
not  saponi- 
fied by  boil- 
ing alkali 
or  acid. 

White 
needles. 

Large  flat 
needles. 

Long  lustrous 
needles. 

Moderately  sol- 
uble      white 
needles,  con- 
taining 1  aq. 

Long,  very  thin 
prisms,    con- 
taining 1  aq. 

Thin  anhydrous 
plates;  readily 
soluble. 

Anhydrous  rhom- 
bic    tablets ; 
slightly     sol- 
uble  in  cold 
water. 

Large  anhydrous 
needles. 

Flat  needles  or 
large  tablets. 

^  The  tabic  is  chiefly  drawn  up  from  the  descriptions  of  the  isomeric  xyli- 
dines given  by  R o s c o e  and  Schorlemmer  (iii.  part  i v.  page  406).    The 


58 


XYLIDINES. 


TJie  modifications  of  xylidine  produced  by  nitrofying  the  xylenes 
of  coal-tar  naplitlia  and  reducing  the  nitro-derivatives  are  chiefly 
a-orthoxylidine,  a-metaxylidine,  and  paraxylidine,  but  two  of  the 
other  isomers  are  also  said  to  be  produced.  Only  the  a-meta- 
modification  is  of  any  value  for  the  manufacture  of  azo-colouring 
matters,  and  of  the  cumidines,  C0H2(CH2)3.NH2,  which  are 
prepared  by  heating  xylidine  hydrochlorides  with  wood  spirit. 
On  this  account,  the  useless  isomers  are  removed  as  far  as  possible 
from  the  metaxylene  before  nitrofying  (Vol.  II.  page  482),  and 
in  fact  the  presence  of  even  a  few  units  per  cent,  of  orthoxylene 
will  occasion  coii?iderable  practical  inconvenience  by  the  formation 
of  tarry  matters  during  its  conversion  into  xylidine.  On  the  other 
hand,  commercial  xylidine  often  contains  as  much  as  25  j)er  cent, 
of  paraxylidine.  v-metaxylidine  (1  :  3  :  2)  is  prepared  by  convert- 
ing commercial  xylidine  into  the  sulphate,  which  is  allowed  to 
crystallise,  and  the  base  liberated  from  the  mother-liquor  by  alkali. 
The  fraction  distilling  between  212°  and  216°  is  heated  with 
acetic  anhydride.  The  v-m  eta-acetxylidide  formed  is  not 
acted  on  by  boiling  for  several  hours  with  four  times  its  weight  of 
dilute  sulphuric  acid  containing  25  per  cent,  of  HgSO^,  but  its 
isomers  are  decomposed.  On  cooling,  the  unchanged  acetyl-com- 
pound  separates,  and  after  recrystallisation  from  hot  water  melts  at 

characters  differ  considerably  from  those  attributed  to  the  isomers  by 
Wroblewsky  {Annalen,  ccvii.  91).  Nolting  and  Pick  {Berichte,  xxi. 
3150),  however,  consider  that  Wroblewsky's  -y-orthoxylidine  was  simply 
impure  ■y-nietaxylidine,  and  give  the  following  table  of  characters  of  xylidine 
salts : — 


v-Orthoxylidine. 

as-Orthoxylidine. 

r-Metaxylidine. 

Wroblewsky's 

so-called 
Orthoxylidine. 

Hydrochloridk,    . 

-t-lHaO 

4-IH2O 

-I-JH2O;  needles 

-f-JHaO 

Solubility  in  100  of 
water  at  18°  C, 

11-2 

Very  soluble. 

9-2 

Very  soluble. 

Nitrate,  . 

Anhydrous. 

Anhydrous. 

Anhydrous. 

Anhydrous. 

Solubility  in  100  of 
water  at  18°  C, 

6-6 

0-4 

2-2 

27 

XoRMAL  Sulphate, 

Anhydrous. 

Anhydrous. 

Anhydrous. 

Anhydrous. 

Solubility  in  100  of 
water  at  18°  C, 

1-4 

5-6 

Very  soluble. 

... 

ACID  Sulphate,     . 

Is  not  formed 

under  ordinary 
tions. 

+  2i  HaO 

+  2i  H2O 

Solubility  in  100  of 
water  at  18°  C, 

6-2 

Very  soluble. 

XYLIDINES.  59 

176''*8  C.  On  heating  it  for  some  time  to  200°  C,  with  three  parts 
of  sulphuric  acid  containing  70  per  cent,  of  HgSO^,  the  sulphate 
of  u-metaxylidine  is  formed.  This  salt  differs  from  the  sulphate  of 
the  isomeric  xylidines  in  its  very  ready  solubility  in  water. 

a-Orthoxylidine  (1:2:4)  is  the  only  modification  of  xylidine 
which  is  solid  at  ordinary  temperatures.  By  gradually  evaporat- 
ing its  solution  in  petroleum  ether,  it  is  obtained  in  thick  mono- 
clinic  prisms,  but  when  rapidly  deposited,  or  caused  to  solidify 
quickly,  it  forms  transparent  vitreous  tablets.  It  melts  at  49°,  and 
is  sparingly  soluble  in  cold  water,  but  readily  in  hot  water,  and  also 
in  alcohol  and  ether.  Its  aqueous  solutions  are  not  coloured  by 
bleaching  powder  solution.  The  hydrochloride  is  readily  soluble 
in  water,  but  only  slightly  in  strong  hydrochloric  acid ;  its  aqueous 
solution  imparts  an  intense  yellow  colour  to  fir-wood. 

a-MetaxijUdine  (1:3:4),  or  ordinary  xylidine,  is  best  obtained 
by  converting  commercial  xylidine  into  the  hydrochloride  and 
crystallising  the  product  from  water.  Both  the  hydrobromide  and 
hydrochloride  are  only  slightly  soluble  in  cold  water.  The  last 
traces  of  impurity  can  be  removed  from  metaxylidine  by  convert- 
ing it  into  the  acetyl-derivative,  and  recrystallising  this  body  from 
benzene  till  it  has  a  melting-point  of  129°.  It  is  then  decomposed 
by  sulphuric  acid. 

Paraxylidine  (1  : 4  :  2)  has  a  specific  gravity  of  0  9 80.  It  is 
prepared  by  treating  commercial  xylidine  with  fuming  sulphuric 
acid  containing  sufficient  sulphuric  Mihydride  to  convert  the  bases 
into  sulphonic  acids.  The  mixture  is  heated  to  100°  for  some 
time,  allowed  to  cool,  and  the  solid  mass  pressed  under  water  to 
separate  metaxylidine-sulphonic  acid  in  the  crystalline  state  ;  or  the 
hot  liquid  is  poured  upon  ice,  when  the  metasulphonic  acid,  being 
with  difficulty  soluble  in  dilute  sulphuric  acid,  crystallises  out. 
The  mother-liquor  is  neutralised  with  chalk,  filtered,  precipitated 
with  sodium  carbonate,  and  again  filtered.  On  concentrating  the 
filtrate,  the  sodium  salt  of  paraxylidine-sulphonic  acid 
separates  in  nacreous  plates,  which  are  washed  with  a  little  cold 
water  to  free  them  from  traces  of  the  readily  soluble  meta-sul- 
phonate.  The  salt  yields  paraxylidine  on  dry  distillation  with  am- 
monium chloride,  while  the  sodium  salt  of  metaxylidine-sulphonic 
acid  chars  under  the  same  treatment.  Paraxylidine  may  also  be 
obtained  by  nitrofying  and  reducing  paraxylene,  which  may  readily 
be  prepared  from  commercial  xylene  (Vol.  II.  page  483). 

CuMiDiNES.     Amido-trimethylbenzenes.     0^112(0113)3.  NHg. 

Various  isomerides  of  this  formula  are  known.  The  solid 
variety  of  commercial  cumidine  is  made  by  heating  xylidine  hydro- 
chloride and  methyl  alcohol  together  under  pressure,  to  about  300°. 


60  ANILINE  OILS. 

The  bases  are  liberated  and  converted  into  nitrates,  and  the 
difficultly  soluble  nitrate  of  pseud ocumi dine  separated  from  the 
mother-liquor.  The  base  is  again  liberated  and  distilled.  The 
fraction  passing  over  between  230°  and  240°  crystallises  on  cool- 
ing, and  consists  of  amid  o-p  seudocumene  : — 
(CHg  :  CHg  :  CHg  :  NH2=  1  :  2  :  4  :  5). 
It  crystallises  from  hot  water  in  long  needles,  and  from  alcohol  in 
large  prisms,  melts  at  68°,  and  boils  at  234°-236°.  When  con- 
verted into  diazocumene  it  can  be  used  for  the  preparation  of 
azo-colours  by  reaction  with  naphthol-mono-  and  di-sulphonic  acids. 

IsoDURiDiNE.     Amido-tetramethylbenzene.     CgH(CH3)4.NH2. 

When  the  hydrochloride  of  pseudocumidine  is  heated  with 
methyl  alcohol  to  300°,  the  hydrochloride  of  isoduridine  is  formed. 
The  free  base,  which  also  occurs  among  the  bye-products  of  the 
manufacture  of  pseudocumidine.  is  an  oily  liquid  which  boils  at 
250°-253°,  and  solidifies  on  cooling  to  crystals  which  melt  at  14°. 

Amido-pentamethylbenzene.       Cg(CH3)^.K^Il2. 

This  base  is  obtained  by  heating  dimethyl-a-pseudocumidine 
with  methyl  iodide.  It  forms  large  white  needles,  melting  at  151° 
and  boiling  at  277°. 

Aniline  Oils. 

The  term  "  aniline  oils"  is  applied  commercially  to  all  the 
different  varieties  of  aniline  manufactured  on  a  large  scale,  equally 
whether  the  product  in  question  consists  of  nearly  pure  aniline,  of 
toluidine,  or  of  a  mixture  of  the  two.  The  method  of  manu- 
facturing the  different  varieties  of  aniline  oil  is  substantially  the 
same,  the  composition  of  the  product  depending  on  that  of  the 
hydrocarbon  employed.  The  details  of  the  method  of  manu- 
facture are,  of  course,  subject  to  variation,  but  the  following  is  an 
outline  of  the  method  pursued  in  a  well-known  aniline  works : — 
Crude  coal-tar  naphtha  is  redistilled  to  a  temperature  of  170°  C. 
The  product  of  the  distillation,  called  "once-run  naphtha,"  is 
treated  with  strong  sulphuric  acid  (sp.  gr.  1*845)  which  removes 
the  bases,  hydrocarbons  of  the  ethylene  and  crotonylene  series,  and 
some  of  the  highei  homologues  of  benzene.  A  subsequent  treat- 
ment with  milk  of  lime  or  caustic  soda  eliminates  the  phenols  and 
other  bodies  of  an  acid  character.  The  purified  oil  is  washed  with 
water  and  redistilled  to  obtain  "50/90  benzol,"  and  this  when 
fractionated  with  the  acid  of  a  dephlegmating  column  at  once 
yields  99  per  cent,  benzol,  toluol,  and  solvent  naphtha  (compare 
Vol.  II.  page  487).  Solvent  naphtha  is  now  generally  further 
treated  for  the  isolation  of  xj'lene,  but  the  benzols  and  toluol 
are  directly  converted  into  the  nitro-compounds  by  placing  them 


MANUFACTURE   OF  ANILINE.  61 

in  a  vessel  surrounded  with  cold  water,  and  gradually  running  in  a 
cold,  previously  made  mixture,  of  150  per  cent,  by  weight  of  nitric 
acid  of  1*4  specific  gravity  with  200  per  cent,  of  concentrated  sul- 
phuric acid.  When  the  reaction  is  complete  the  mixture  is  allowed 
to  stand,  and  the  lower  layer  of  acid  is  tapped  off  and  concentrated 
again  in  glass  for  repeated  use.  The  nitrohenzol  is  washed  several 
times  with  caustic  soda,  and  then  treated  with  open  steam  to  drive 
off  unchanged  benzol  and  "light  stuff."  The  nitrobenzol  (or 
nitrotoluol  obtained  in  a  precisely  similar  manner)  is  then  placed 
in  a  still  with  hydrochloric  acid,  and  borings  or  filings  of  grey  cast 
iron  added  gradually.  High-pressure  steam  is  blown  in,  and  the 
nitrobenzol  which  distils  over  is  separated  from  the  condensed 
water,  and  returned  to  the  still  until  the  complete  solubility  of  the 
distilled  oil  in  hydrochloric  acid  shows  that  the  reaction  is  complete. 
Milk  of  lime  is  then  introduced,  and  the  liberated  aniline  distilled 
off  by  the  aid  of  steam.  Aniline  sinks  to  the  bottom  of  the  con- 
densed water,  but  when  toluidine  is  being  made  the  oil  floats  on 
the  surface.  The  condensed  water  contains  from  2  to  3  per  cent, 
of  dissolved  bases,  and  is  converted  into  steam  for  the  aniline  stills. 
The  iron  is  converted  into  a  black  paste,  consisting  chiefly  of  FegO^, 
which  is  sold  for  purifying  gas.  The  aniline  oil  is  distilled  to 
separate  water,  &c.  The  addition  of  lime  to  liberate  the  aniline  is 
not  strictly  necessary,  and  in  many  works  it  is  omitted.  The  first 
reaction  seems  to  be  : — 

CeHg.NOg  +  Feg  -f-  6HC1  =  SFeClg  +  CgHg.NHg  +  2H2O. 

The  ferrous  chloride  formed  also  acts  as  a  reducing  agent,  being 
converted  into  ferric  chloride,  which  in  presence  of  water  gives 
ferric  oxide  and  aniline  hydrochloride.  The  end-products  are 
chiefly  aniline,  ferroso-ferric  oxide,  and  a  weak  solution  of  ferrous 
chloride.  The  hydrochloric  acid  seems  to  act  chiefly  as  a  carrier, 
so  that  the  general  reaction  may  be  represented  by  the  equation : — 
4C6H5.NO2  +  9Fe4-  4H2O  =  SFcgO^-l-  4C6H5.NH2.  Acetic  acid  was 
formerly  employed  in  place  of  hydrochloric  acid,  but  its  use  is  now 
almost,  if  not  entirely,  obsolete.  Its  use  in  too  large  a  proportion 
tended  to  the  formation  of  acetanilide.  Too  large  an  excess 
of  iron,  or  its  too  rapid  addition,  may  cause  loss  from  a  reproduction 
of  benzene,  while  deficiency  of  both  iron  and  acid  favours  the 
production  of  azo-benzene. 

Composition  and  Assay  op  Aniline  Oils. 

There  are  three  leading  kinds  of  aniline  oil  now  recognised 
in  the  market,  namely: — (1)  Pure  aniline  oil;  (2)  aniline  oil  for 
red;  and  (3)  toluidine.  The  demand  for  xylidine  for  the 
manufacture  of  azo-reds  has  considerably  influenced  the  character 


62  VARIETIES   OF  ANILINE   OIL. 

of  commercial  aniline;  since  the  50/90  benzol,  which  was 
commonly  used  for  the  manufacture  of  "  aniline  for  red,"  formerly 
contained  a  notable  quantity  of  xylene,  which  is  now  removed 
and  converted  separately.  Since  the  employment  of  dcphlegmating 
columns  has  become  usual,  benzene  and  toluene  of  almost  constant 
boiling-points  have  been  manufactured.  From  the  pure  hydro- 
carbons the  corresponding  bases  are  prepared,  while  from  the  inter- 
mediate oil,  containing  about  25  per  cent,  of  benzene  and  75  of 
toluene,  an  aniline  oil  for  red  is  manufactured,  which  contains 
about  25  per  cent,  of  aniline,  from  20  to  25  of  paratoluidine, 
and  45  to  50  per  cent,  of  orthotoluidine.^ 

In  addition  to  the  foregoing  leading  qualities  of  aniline  oil, 
products  of  very  varying  composition  and  degrees  of  purity  have 
to  be  dealt  with  by  the  dye-manufacturer.  Thus  in  making 
magenta  by  the  arsenic  acid  process,  fully  one-fourth  of  the 
aniline  distils  off  and  is  condensed.  But  this  recovered  aniline 
is  found  on  rectification  to  have  a  considerably  higher  density 
than  the  original  oil  (1-015  to  1*009  against  1'0075),  and  to 
consist  almost  entirely  of  aniline  and  orthotoluidine,  whereas 
the  original  oil  contained  from  15  to  25  per  cent,  of  para- 
toluidine. This  is  either  employed  for  the  manufacture  of 
safranine  or  very  red  shades  of  blue,  or  crude  paratoluidine  is 
added  to  it  in  such  proportion  as  to  bring  it  approximately  to 
the  original  composition.  Similarly,  in  the  manufacture  of 
magenta  by  the  nitrobenzene  process,  the  recovered  aniline 
contains  notable  quantities  of  nitrobenzene,  while  from  other 
processes  methylated  and  ethylated  anilines  are  obtained.  Re- 
covered anilines  are  deeper  in  colour  and  of  greater  body  than 
unused  oils,  and  often  have  a  strong  and  somewhat  characteristic 
odour.  They  are  rarely  met  with  outside  the  colour- works  in 
which  they  have  their  origin. 

On  next  page  is  a  tabulated  list  of  the  more  important  or 
frequently-occurring  constituents  of  aniline  oils.^  With  the  ex- 
ception of  aniline  and  its  homologues,  and  the  substituted  anilines, 
very  little  is  known  respecting  the  effect  of  the  bodies  formulated 
in  the  table  on  the  colouring  matters  produced.  For  the  most  part 
the  objectionable  impurities  are  got  rid  by  fractionating  the  crude 
aniline  oil. 

^  The  composition  of  aniline  oil  for  red  is  often  judged  of  by  the  consumer 
solely  from  the  specific  gravity,  and  he  or  the  aniline-maker  adjusts  it  accord- 
ingly by  adding  aniline  or  toluidine  to  the  crude  oil  as  the  gravity  may 
indicate. 

2  Hell  and  Rockenbach  {Ber.,  xxii.  505)  have  investigated  some  other 
non-basic  constituents  of  aniline  and  toluidine  tailings. 


CONSTITUENTS   OF  ANILINE   OILS. 


63 


Name. 

Formula. 

Melting- 
Point 'C. 

Boiling- 
Poirit 'C. 

Remarks. 

Aniline,    . 

C6H6.NH2 

-  8 

183-7 

See  page  43. 

T^i„5     (ortho-;  1 :2 

)                                         ( 

below  -  20 

199 

-  See  page  52. 

C6H4(CH3).NH2                ] 

below -13 

197 

)                                        i 

45 

198 

Xylidine       (several 

isomers), 

Cen3(CH3)2.NH2 

... 

212-226 

See  page  57. 

Cumidine      (several 

isomers,       chiefly 

Pseudocumidine), 

C6Ho(CH3)3.NH3 

63 

235 

See  page  60. 

Methyl-aniline, 

C6H5.NH(CH3) 

... 

192 

See  page  73. 

Dimethyl-aniline,     . 

C6H5.N(CH3)o 

0-5 

192 

See  page  74. 

Ethyl-aniline,  . 

C8H5.NH(C2H5) 

... 

204 

See  page  73. 

Diphenylamine, 

CeHg-NHCCeHs) 

54 

302 

See  page  79. 

Acetanilide,      . 

C6H5.NH(C2n30) 

112 

295 

See  page  68. 

Acetotoluide  ^^^^ho- 

[  C6H4(CH3).NH(C2H30)| 

65-66 
147 

302-304 
300-307 

(Produced  by  action  of 
•<     heat    on   toluidine 
(    acetate. 

Nitranilines,     . 

C6H4(N02).NH2. 

... 

... 

From  imperfect  reduc- 
tion  of  dinitroben- 
zene. 

Paraniline, 

C12H14N2 

192 

330 

Xenylamine,    . 

C,2H9.NH2 

45 

322 

... 

Phenylene  -  diamine 

(para-),  . 

C6H4:(NH2)2 

C3 

287 

Reduction  of  dinitro- 
benzene  (page  87). 

Toluylene-diamine 

(para-),  . 

C6n3(CIl3):(NH2)2 

99 

283-285 

See  page  88. 

Azobenzene,     . 

C6H5.N2.C6H5 

65 

293 

Imperfect     reduction 
of  nitrobenzene. 

Nitrobenzene,  . 

C6H5.(N02) 

3 

210 

Vol.  II.  page  476. 

(  ortho- 

^C6H4(N02)2                          i 

118 

Monoclinic  tables. 

Dinitro-      J    meta- 
benzenesl 

90 

Long  needles  or  thin 
rhombic  tables. 

I  para- 

172 

... 

Monoclinic  needles. 

■^T.^.„^            (  ortho- 

i                         ( 

below -20 

"223 

Sp.  gr.  1-163  at  23°-5. 

|.C6H4(CH3XN02)            1 

16 
54 

230 
238 

Sp.  gr.  1-168  at  22°. 

Benzene,  . 

CeHs 

5-5 

80-5 

Vol.  II.  page  469. 

Toluene,   . 

C6H6(CH3) 

below -20 

111 

Vol.  II.  page  479. 

Amidothiophene,     . 

C4H3S.NH2 

... 

... 

... 

Paraffins,  . 

i 

CaHan+a 

... 

Especially   in   aniline 
oils     derived    from 
cannel-tar  benzols. 

The  assay  of  aniline  oils  is  usually  limited  to  observations  of  the 
colour,  odour,  and  specific  gravity,  supplemented  by  a  careful  frac- 
tional distillation  and  tests  for  water,  nitrobenzene,  hydrocarbons,  &c. 

The  specific  gravity  of  aniline  oil  is  a  valuable  indication 
of  its  composition.  The  observation  must  be  made  by  the  plummet 
or  specific-gravity  bottle  at  exactly  15°  C,  and  the  result  referred 
to  water  at  the  same  temperature  taken  as  unity.^ 

ip.  Schoop  {Chem.  ZeiL,  ix.  178  ;  Jour.  Soc.  Chem.  Ind.,  v.  178)  gives 
the  density  of  pure  aniline  as  1*0377  at  1°  C;  orthotoluidine  as  1*0143;  and 
paratoluidine  as  1  '0045  at  the  same  temperature  ;  the  coefficient  of  expansion 
being  in  each  case  0*00081  for  1°  C. 


64  EXAMINATION   OF   ANILINE   OILS. 

The  following  figures  represent  the  densities  as  thus  observed  : — 

Specific  gravity  at  15°  C. 
Pure  aniline,      .         .  .  .  TO  2  6  8. 

Aniline  oil  for  red,      .  .  .  1*0075  to  1-0012. 

Orthotoluidine,  ....  I'OOST. 

Mixture  of  equal  parts  of  ortho-  \         .0075 

and  para-toluidine,  .  .  J 

Paratoluidine,    ....  Solid. 

The  odour  of  pure  aniline  is  very  different  from  that  of  the 
toluidines.  The  presence  of  toluidine  in  aniline  is  indicated  by 
the  density  of  the  sample,  its  diminished  solubility  in  dilute  alcohol 
(page  65),  and  by  the  results  of  the  fractional  distillation  (page 
65).  In  addition  to  these  characters,  the  following  tests  are 
sometimes  of  service  : — 

Pure  aniline  affords  no  rosaniline  on  treatment  with  oxidising 
agents,  but  if  toluidine  be  present  magenta  is  readily  formed.  The 
test  is  best  made  by  mixing  5  c.c.  of  the  sample  of  aniline  with  an 
equal  measure  of  a  concentrated  solution  of  arsenic  acid,  containing 
about  75  per  cent,  of  AsgOg  and  having  a  density  of  2 '04.  The 
mixture,  contained  in  a  small  flask  or  long  test-tube,  is  immersed 
ill  a  paraffin-bath  heated  to  180°  C.  The  mixture  rapidly  changes 
in  colour,  and  swells  considerably.  When  the  action  is  complete, 
the  contents  of  the  tube  acquire  a  metallic  bronze  appearance  and 
no  longer  intumesce.  The  product  is  treated  with  boiling  water, 
when,  if  the  sample  contained  toluidine,  arseniate  of  rosaniline 
dissolves  and  communicates  an  intense  crimson  colour  to  the  liquid. 
Neither  pure  aniline  nor  toluidine  alone  gives  this  reaction. 

If  a  sample  of  commercial  aniline  be  mixed  with  some  solid 
magenta  and  a  few  drops  of  glacial  acetic  acid,  and  the  whole 
heated  to  180°  C,  as  described  above,  ammonia  is  abundantly 
evolved,  and  in  a  short  time  the  mixture  becomes  intensely  blue 
from  the  formation  of  trip  h  enyl-ros  anil  in  e.  With  pure 
aniline  the  blue  is  very  pure  in  shade,  but  when  toluidine  or  xyli- 
dine  is  treated  in  a  similar  manner  the  product  is  intensely  purple, 
and  a  mixture  of  the  bases  gives  proportionate  intermediate 
shades  of  colour.  If  a  little  of  the  "  melt "  be  withdrawn  from  the 
tube,  diluted  considerably  with  alcohol,  a  few  drops  of  acetic  acid 
added,  and  then  streaked  on  white  filter-paper  by  means  of  a  glass 
rod,  the  purple  tint  is  readily  observed,  especially  if  the  paper  be 
held  up  before  a  gas-flame. 

A  valuable  indication  of  the  general  composition  of  an  aniline 
oil  is  obtained  by  submitting  the  sample  to  fractional  distillation, 
and  noting  the  proportions  of  distillate  obtained  at  various  tem- 


ASSAY   OF   ANILINE  OILS. 


65 


peratiires.  The  distillate  may  be  measured  after  each  rise  of  5 
degrees  in  the  boiling-point  of  the  sample,  or  the  temperature  may 
be  observed  when  each  consecutive  5  or  10  per  cent,  fraction  has 
passed  over.  The  latter  is  the  plan  now  commonly  adopted,  100 
c.c.  of  the  sample  being  employed,  and  the  arrangement  of  the 
apparatus  being  exactly  the  same  as  in  the  fractional  distillation  of 
benzols  (Vol.  II.  page  495). 

The  heat  is  applied  cautiously  at  first,  in  order  to  dissipate  any 
water.  ^^Tien  this  is  effected,  which  will  be  known  by  the  rapid 
rise  of  the  thermometer,  the  heat  is  so  regulated  that  the  distillate 
shall  fall  in  distinct  drops,  about  sixty  per  minute.  With  each 
increase  of  10  c.c.  in  the  volume  of  the  distillate  the  temperature 
indicated  by  the  thermometer  is  observed  and  recorded,  the  process 
being  continued  till  90  or  95  c.c.  have  passed  over. 

A  very  simple  test  for  aniline  oils  was  devised  and  communicated 
to  the  writer  by  the  late  B.  Nickels,  who  found  it  to  give  useful 
results,  and  to  indicate  differences  between  samples  not  readily 
distinguishable  by  the  ordinary  fractional  distillation  process.  The 
test  is  based  on  the  greater  solubility  in  dilute  alcohol  of  aniline  as 
compared  with  toluidine  and  xylidine,  and  is  thus  performed : — 
6  c.c.  measure  of  the  sample  is  taken  with  a  pipette  and  diluted  to 
40  c.c.  with  methylated  spirit.  Distilled  water  is  then  gradually 
added  from  a  burette,  with  constant  shaking,  till  a  permanent  tur- 
bidity is  produced,  when  the  volume  of  water  employed  is  noted. 
Operating  in  this  way,  a  sample  of  very  pure  aniline  required  126 
c.c.  of  water  to  produce  permanent  turbidity.  The  following  figures, 
obtained  by  B.  Nickels  in  1881,  show  the  results  yielded  by  three 
typical  specimens  of  commercial  aniline  as  then  manufactured : — 


A. 

B. 

C. 

Pure  Aniline. 

Heavy  Aniline. 

Toluidine. 

Colour, 

Pale  amber. 

Amber. 

Deep  brown. 

Specific  gravity  at  15°-5  C, . 

1-025 

1-011 

1-002 

Water  required  for  precipitation, 

106-4  C.C. 

73-7  C.C. 

63-2  c.c. 

•c. 

•c. 

•c. 

10  per  cent,  distilled  over  at 

183i 

189 

195 

20        „               „               ,,         .        . 

183i 

1891 

1951 

SO        ..              „              „         .        . 

1831 

190 

196 

40       „              „              „          .        . 

184 

191 

196^ 

50        „               „               „          .        . 

184i 

191J 

197 

60        „               „               „          .        . 

184 

192i 

197i 

70        „               „               „          .        . 

184 

193 

198 

80        „                ,                          .        . 

184 

1941 

198i 

90        „               .,               „          .        . 

lai 

197 

1991 

95        „               „               „          .        . 

201 

Sample  A  was  a  fair  commercial  specimen  of  the  quality  known 
"pure  aniline,"  and  actually  contained  some  95  per  cent 

Vr»T.      TIT      "DA  1301    TT  IT 


as  "p 

VOL.  III.  PART  II. 


66 


DISTILLATION   OF   ANILINE   OILS. 


of  real  aniline.  An  article  of  this  high  purity  is  required  for  the 
manufacture  of  aniline  blue,  triphenyl-rosaniline  (see 
page  64),  any  notable  admixture  of  toluidine  resulting  in  a  pro- 
duct dyeing  with  reddish  tinge.^ 

The  quality  known  as  "heavy  aniline,"  exemplified  by  B, 
is  a  fair  sample  of  aniline  oil  for  red  (see  page  62).  This 
class  of  aniline  is  produced  from  benzols  containing  a  considerable 
proportion  of  toluene,  and  the  aniline  oil  itself  is  a  mixture  of 
aniline  and  toluidines.  Good  samples  of  aniline  oil  for  red  contain 
from  35  to  42  per  cent,  of  real  aniline,  35  to  50  per  cent,  of 
ortho toluidine,  and  14  to  24  per  cent,  of  paratoluidine. 

K.  J.  Friswell  thinks  100  c.c.  an  undesirably  small  quantity 
for  fractional  distillation.  He  prefers  to  operate  on  250  c.c,  which 
he  distils  in  a  flask  with  a  side-tubulure,  and  he  recommends  an 
observation  of  the  temperature  at  which  the  last  drop  disappears 
from  the  bottom  of  the  flask.  A  naked  flame  is  used,  and  a  few 
fragments  of  platinum  wire  or  fire-brick  added  to  the  contents 
of  the  flask.  The  following  figures  were  obtained  by  Friswell 
(Thorpe's  Diet.  Applied  CJiem.y  i.  165)  by  the  examination  of 
commercially  pure  aniline. 


No.  1. 

No.  2. 

No.  3.           1 

Specific  gravity  at  15'  C,    .     .     .     . 

10  per  cent,  over  at, 

20       „              „        

30       „               „        

S    ;:       ;;:::::: 
fo    :;       :;    :;:•:: 

80        „               „        

90        „               „        

Dry  at, 

1-02710 

°C. 
184-7 
184-7 
184-7 
184-7 
184-8 
184-9 
185-0 
185-1 
185-1 
186-7 

l-02«84 

°C. 
184-6 
184-8 
184-8 
184-8 
184-8 
184-8 
184-8 
184-8 
184-8 
186-8 

1-02690 
"C. 
184  6 
184-6 
184-7 
184-7 
184-8 
184-8 
184-9 
184-9 
185-0 

Any  neater  present  in  aniline  oil  will  be  found  in  the  very  first 
portions  (first  fraction  of  10  per  cent.)  whenever  the  sample  is 
submitted  to  distillation.  It  takes  the  form  of  globules,  which 
are  not  miscible  with  the  next  fraction  of  the  distillate  nor  with 
petroleum  spirit.  Water  may  exist  in  aniline  in  any  proportion 
from  a  trace  up  to  3  or  4  per  cent.,  but  a  good  commercial  recti- 
fied specimen  should  not  contain  more  than  0'5  per  cent.  Aniline 
is  readily  soluble  in  a  strong  aqueous  solution  of  aniline  hydro- 

^  In  good  samples  the  boiling-points  hold  closely  together,  differing  by  one 
or  two  degrees  only.  Insqualities  or  jumps  in  the  boiling-point,  especially  at 
the  beginning  and  end  of  the  distillation,  indicate  badly-made  samples  oi 
mixtures. 


IMPURITIES  IN   ANILINE   OILS.  67 

chloride.  A  solution  of  the  kind,  of  1"08  specific  gravity,  is  stated 
by  Watson  Smith  to  be  sometimes  sold  as  aniline  oil,  which  in 
colour  and  taste  it  closely  resembles.  Such  a  fraud  would  be  at 
once  detected  on  distillation. 

Benzene,  toluene,  and  other  hydrocarbons  will  separate  when  the 
first  fraction  of  10  per  cent.  (10  c.c.)  is  treated  with  an  equal  volnme 
or  slight  excess  of  hydrochloric  acid,  and  water  added  to  100  or 
150  c.c.  They  assume  the  form  of  oily  globules  which  float  even 
on  diluting  the  liquid.  The  best  samples  of  pure  aniline  show  only 
a  slight  opalescence  when  thus  treated,  but  the  smell  of  the 
"  light  stuff  "  (Vol.  II.  page  488)  is  always  perceptible.  In  recovered 
anilines  these  impurities  exist  to  a  notable  extent,  since  they  sur- 
vive the  reactions  by  which  the  bases  are  consumed.  Aniline 
for  red  usually  contains  somewhat  more  hydrocarbons  than  pure 
aniline. 

Nitrobenzene  and  nitrotoluene  may  be  recognised,  even  when  mere 
traces  are  present,  by  the  milky  appearance  of  the  liquid  produced 
by  saturating  1 0  c.c.  of  the  original  sample  of  oil  with  hydrochloric 
acid.  On  diluting  the  liquid  with  water,  and  leaving  it  at  rest  for 
some  hours,  any  considerable  quantity  of  nitrobenzene  will  collect 
at  the  bottom  in  the  form  of  oily  globules,  which,  after  separating 
the  acid  liquid,  may  be  identified  by  the  smell  and  other  char- 
acters. Still  smaller  quantities  of  nitrobenzene  may  be  recognised 
if  the  "  tailings"  be  operated  upon,  instead  of  the  original  sample. 
Nitrobenzene  occurs  more  frequently  in  magenta-aniline  and  tolui- 
dine  than  in  the  oils  of  lower  boiling-point. 

Nitrobenzene  is  also  indicated  by  the  yellow  colour  of  the  froth 
produced  when  the  sample  is  violently  agitated. 

Acetanilide  and  acetotoluide  were  impurities  characteristic  of 
aniline  prepared  by  the  reduction  of  nitrobenzene  with  acetic  acid 
and  iron,  but  are  now  rarely  met  with  in  aniline  oils.  In  any 
case  they  would  become  concentrated  in  the  "  tailings,"  together 
with  phenylene-diamine,  azobenzene,  paraniline,  "  xenylamine,"  &c. 

Aniline  tailings  is  the  name  applied  to  the  least  volatile  portion 
of  aniline  oils.  They  contain  little  or  no  aniline ;  some  toluidine, 
xylidine  and  cumidine ;  nitrobenzene  and  its  homologues ;  and 
some  or  all  of  the  bye-products  tabulated  on  page  63  which  boil 
above  200°  C. 

The  composition  and  special  methods  of  examination  of  com- 
mercial toluidine  are  described  on  page  54  e^  seq. 

Anilides. 

The  anilides  are  derivatives  of  aniline  in  which  one  or  both 
of  the  hydrogen-atoms  of  the  amido-group  are  replaced  by  acid- 


68  ANILIDES. 

radicals.  The  homologues  of  aniline  yield  similar  derivatives  (e.^., 
aceto-toluide,  page  52).  The  most  important  and  typical  mem- 
ber of  the  class  isacetanilide    or    phenylacetamide  : — 

C,H,.NH(C,H30);  or  C^H^O.NHCC.H,) . 

A  number  of  derivatives  of  acetanilide  have  been  prepared,  and 
certain  of  them  have  found  some  employment  as  analgesics  and 
antipyretics,  as  for  instance  : — 

Acetanilide.    Phenylacetamide.    Antifebrin.    CgH5.NH(C2H30). 
Bromacetanilide.    Antiseptin.    Bromi-  )       ^  ^^  ^j  ^.^  ^  ^. 
nated  antifebrin.     (Page  71.)  f      ^HBr.N4H(C2H30). 

Methylacetanilide.    Exalgin_    Methy-  j    c,H,.N(CH3)(C,H30). 

lated  antifebrin.     (Page  71.)  j       6    5     \       3/v   2    3    / 

Aceto-amidophenol.  Hydroxy-antifebrin,  CgH4(OH).NH(C2H30). 
Aceto-anisidine.        Methacetin.      )      p  -rr  /n  nir  \  Arw/r"  tt  r\\ 

Methoxy-antifebrin.  (Page85.)  /     ^^.(O.CHg^NHCC^HgO). 

Acet-phenethidine.      Phenacetin.  |     n  tt  /r\n  tt  \  attt/z-i  tt  rw 
Ethoxy-antifebrin.   (Page  81.)  |    ^e^^iO.C.U.yiSliiC.'Kfi). 

Amido-phenacetin.   Phenocoll.   C6H4(O.C2H5).NH(C2H20.NH2), 

Most  of  these  bodies  are  described  in  the  following  pages.  The 
relationship  of  antifebrin  to  hypnone,  hydracetin  (pyrodine),  and 
phenyl-urethane,  is  shown  by  the  following  formulae : — 

Acetophenone.  Hypnone  (Part  I.  page  23).  CgH5.(CO.CH3). 
Acetanilide.     Antifebrin  (see  below).  C6H5.NH.(CO.CH3). 

"^Tpl^e'Ts  )^'^''''''''    ^^^"^""^^'  \    CA.NH.NH.(C0.CH3). 

"^ThS^^^^^  ^^'"l     CgH,NH.NH.(C,HA). 

Phenyl-urethane.    Euphorin.    (Page  72.)  C6H5.NH.(CO.O.C2H5). 

Acetanilide.     Phenylacetamide.     CgH5.NH(C2H30). 

This  substance  was  originally  obtained  by  the  action  of  acetyl 
chloride  on  aniline.  It  is  more  conveniently  prepared  by  boiling 
aniline  with  glacial  acetic  acid  for  many  hours  under  an  inverted 
condenser,  until  the  product  solidifies  on  cooling.  The  mass  is 
then  melted  and  poured  into  water,  to  remove  unconverted  aniline 
and  acetic  acid.  It  may  be  purified  by  distillation  and  crystal- 
lisation from  alcohol,  benzene,  or  hot  water,  from  which  it  separates 
in  colourless  unctuous  laminae,  resembling  boric  acid,  soluble  in 
about  190  parts  of  cold  or  18  of  boiling  water.  Acetanilide  is 
odourless,  but  produces  a  slight  burning  sensation  on  the  tongue. 
It  occurs  commercially  as  a  crystalline  powder  or  scales.  It  melts 
at  112°-113°,   and   distils   unchanged   at  295°  C.      Acetanilide 


ACETANILIDE.  69 

dissolves  in  3|  parts  of  alcohol,  and  is  very  soluble  in  ether, 
chloroform,  and  benzene,  yielding  neutral  solutions. 

Acetanilide  is  a  weak  base.  The  hydrochloride  is  obtained  by 
passing  hydrochloric  acid  gas  through  a  solution  of  acetanilide  in 
acetone.  It  forms  needles  which  are  decomposed  into  their  con- 
stituents by  water,  and  gradually  converted  into  acetic  acid  and 
aniline  hydrochloride  on  exposure  to  moist  air. 

Acetanilide  dissolves  in  strong  sulphuric  acid  without  change  of 
colour.  On  treating  the  solution  with  nitric  acid,  the  acetanilide 
is  converted  chiefly  into  ^am-nitroacetani  1  ide  (page  50), 
some  of  the  ortho-Q.om^o\mdi  and,  in  presence  of  a  large  excess  of 
sulphuric  acid,  a  little  of  the  meto-compound  being  also  formed. 
Nitrous  acid,  passed  into  its  acetic  acid  solution,  converts  acetani- 
lide into  an  unstable  nitrosamine,  C6H5.]S'(C3H30)(NO). 
When  heated  with  zinc  chloride  to  about  250°,  acetanilide  yields 
flavaniline,  C^gHi^NgjIICl  (Part  I.  page  245).  Treated  in  alcoholic 
solution  with  sodium  ethylate,  acetanilide  yields  a  sodium 
derivative,  CgHg.NNaCgHgO,  but  when  this  is  boiled  with 
water  it  splits  into  aniline  and  sodium  acetate.  Acetanilide 
behaves  like  aniline  on  treatment  with  caustic  alkali  and  chloro- 
form (page  46),  and  the  formation  of  the  disagreeably  smelling 
isonitrile  is  a  delicate  reaction  for  its  presence  (compare  page  83). 

Acetanilide  behaves  like  aniline  when  treated  with  phenol  and 
solution  of  bleaching  powder  (page  45). 

When  treated  with  a  solution  of  potassium  chlorate  in  strong 
sulphuric  acid,  acetanilide  gives  a  red  coloration,  changed  to  yellow 
on  dilution.  With  a  crystal  of  a  nitrite  and  a  drop  of  concentrated 
hydrochloric  acid  it  produces  a  yellow  colour,  changing  on  heating 
to  green  and  blue ;  and,  on  evaporating  the  liquid  to  dryness,  an 
orange  residue  is  obtained,  changed  to  red  on  adding  ammonia 
(Vitali). 

When  acetanilide  is  heated  gently  with  mercurous  nitrate,  a 
body  is  produced  which  dissolves  in  alcohol  with  green  colour 
(Y  V  0  n).  If  a  few  centigrammes  of  acetanilide  be  gently  heated 
with  two  or  three  drops  of  a  solution  of  mercurous  nitrate,  and  when 
solution  has  been  effected  two  or  three  drops  of  sulphuric  acid 
added,  a  blood-red  coloration  will  be  produced  (C  e  1 1  a  and 
A  r  z  e  n  o).  The  same  reaction  is  produced  by  phenol,  resorcinol, 
thymol,  and  salicylic,  gallic,  and  tannic  acids,  but  not  by  benzoic 
acid. 

Acetanilide  gives  no  colour-reactions  with  ferric  chloride,  nitrites 
in  very  dilute  solutions,  or  potassium  bichromate  in  aqueous  solu- 
tion.    These  reactions  distinguish  it  from  antipyrine  and  kairine. 

Various  other  colour-reactions  of  acetanilide  have  been  described. 


70  ASSAY   OF   ACETANILIDE. 

As  a  rule,  the  most  satisfactory  method  for  its  positive  identifica- 
tion is  to  heat  the  substance  with  alcoholic  potash^  dilute  with 
water,  and  shake  with  ether.  The  ethereal  layer  is  examined  for 
aniline,  while  the  aqueous  liquid  is  tested  for  an  acetate. 

To  detect  acetanilide  in  urine,  V  u  1  p  i  u  s  boils  the  liquid  with 
hydrochloric  acid,  cools,  extracts  with  ether,  and  tests  the  ethereal 
solution  with  phenol  and  bleaching  powder  solution. 

E.  Ritsert  {Pharm.  Zeit.,  xxxv.  306;  Jour.  Cliem.  Soc,  Iviii. 
1349)  gives  the  following  tests  for  the  purity  of  commercial  acet- 
anilide : — The  sample  should  leave  no  ash  on  ignition,  and  after 
drying  for  two  hours  at  105°,  should  melt  at  114°.  A  higher  or 
lower  melting-point  indicates  the  presence  of  aceto-toluides.  0"1 
gramme  dissolves  in  1  c.c.  of  strong  hydrochloric  acid  to  a  clear 
solution ,  which,  after  a  few  minutes,  precipitates  acetanilide  hydro- 
chloride (methyl-acetanilide  does  not  yield  a  similar  reaction). 
No  change  should  be  produced  on  adding  a  drop  of  nitric  acid, 
which,  after  a  time,  produces  a  yellow  or  brown  coloration  if  j^hen- 
acetin  or  methacetin  be  present.  If  0*1  gramme  be  boiled  in  por- 
tions in  2  c.c.  of  strong  hydrochloric  acid,  the  solution  cooled,  and 
a  drop  or  two  of  chlorine  water  added,  a  fine  blue  coloration  is 
produced.  The  aqueous  solution  of  acetanilide  should  be  free  from 
acid  reaction  (indicating  acetic  acid).  On  boiling  it  and  adding 
ferric  chloride,  a  deep  reddish-brown  colour  should  be  produced, 
destroyed  by  a  mineral  acid.  If  a  drop  of  dilute  solution  of 
potassium'  permanganate  (1  :  1000)  be  added  to  a  boiling  aqueous 
solution  of  1  gramme  of  acetanilide  in  30  c.c.  of  water,  the  pink 
coloration  at  first  produced  should  persist  at  least  five  minutes,  and 
should  not  change  to  yellow  on  again  boiling.  .  Precipitation  at 
this  stage  indicates  the  presence  of  free  aniline,  resinous  products, 
aceto-toluides,  or  other  impurities. 

In  the  additions  (1890)  to  the  British  Pharmacopoeia,  acetani- 
lide is  described  as  melting  at  235°  F.  (  =  112°-8  C),  and  dis- 
solving in  sulphuric  acid  without  coloration.  The  solution  in  18 
parts  of  boiling  water  should  be  clear,  neutral,  and  odourless ;  and 
after  cooling  should  not  be  coloured  on  adding  ferric  chloride. 
This  is  directly  opposed  to  the  experience  of  Ritsert  above  quoted. 
In  the  German  Pharmacopoeia  the  direction  is  to  add  ferric  chloride 
to  a  cold  saturated  solution,  thus  avoiding  the  dissociation  and 
formation  of  acetic  acid  liable  to  occur  on  boiling.  According  to 
the  German  Pharm^acopoeia,  on  heating  with  caustic  alkali  solution, 
acetanilide  gives  off  an  aromatic  vapour,  which,  after  addition  of  a 
drop  of  chloroform  and  renewed  application  of  heat,  is  changed  to 
the  disagreeable  smell  of  the  isonitrile.  Further,  O'l  gramme  of 
acetanilide  should  yield  a  clear  solution  when  boiled  with  1  c.c.  of 


ANTIFEBKIN — EXALGIN.  71 

hydrochloric  acid  for  one  minute ;  and,  after  adding  to  the  liquid 
2  c.c.  of  carbolic  acid,  a  cloudy  red  coloration  should  be  produced 
by  solution  of  bleaching  powder,  changed  to  a  permanent  indigo- 
blue  (i  n  d  o  p  h  e  n  0 1)  on  adding  excess  of  ammonia. 

Acetanilide  has  i)owerful  antipyretic  properties,  and  has  received 
an  extensive  application  in  medicine  under  the  name  of  "anti- 
f  e  b  r  i  n,"^  though  dangerous  symptoms  are  sometimes  produced  by 
it  {Pharm.  Jour.,  [3],  xx.  1059).    The  dose  is  from  3  to  10  grains. 

According  to  S  a  1  z  e  r,  commercial  antifebrin  is  liable  to  certain 
unchanged  aniline,  which  may  be  detected  by  dissolving  the  sample 
in  cold  hydrochloric  acid,  and  pouring  on  the  liquid  a  solution  of 
bleaching  powder.  Pure  acetanilide  yields  a  white  precipitate, 
which  dissolves  on  shaking  the  liquid,  but  after  a  time  coloiirless 
silky  needles  separate.  In  presence  of  aniline  the  well-known 
violet  coloration  is  produced. 

Acetanilide  has  been  used  as  an  adulterant  of  antipyrine  (page 
36).  The  melting-points  of  the  pure  substances  are  nearly  iden- 
tical, but  a  mixture  of  equal  proportions  of  the  two  melts  at  45°  C. 

Of  the  three  isomeric  aceto-toluides  (page  52),  only  the  meta- 
compound  possesses  antipyretic  properties. 

Para-brom-acetanilide,  CQH.fiT.'NJI(CO.Cli^),  has  been  intro- 
duced as  a  remedy  under  the  name  of  "  a  n  t  i  s  e  p  s  i  n."  It  forms 
small  pearly  prisms,  melting  at  164°*5,  and  devoid  of  taste  or  smell. 
It  is  soluble  with  difficulty  in  cold,  but  readily  in  hot  water,  as 
also  in  alcohol  and  ether. 

Acet-methylanilide  or  Methyl-acetaniUde,  CgHg.N(CH3)(C2H30), 
is  prepared  by  warming  together  methylaniline  and  acetyl  chloride. 
The  product  is  boiled  with  water,  when  the  new  body  crystallises 
on  cooling.  Methylacetanilide  has  been  introduced  as  an  anti- 
rheumatic and  analgesic  under  the  name  of  "  e  x  a  1  g  i  n."    In  doses 

^  When  administered  to  rabbits,  acetanilide  is  oxidised  to  para-amidophenol, 
C6H4(OH).NH2,  with  complete  elimination  of  the  acetyl-grouj).  In  dogs  there 
is  a  small  formation  of  para-aniidophenol,  but  the  chief  change  consists  in  a 
simultaneous  oxidation  of  the  aniline-residue  to  ortho-amidophenol,  of  the 
acetyl-group   to  carboxyl,    and   in    the    formntion   of   carbonyl-ortho- 

hydroxyamidophenol,    C6H3(0H)-{    q    |- CO ,  the  anhydride  of  which 

is  excreted  in  the  urine  as  a  sulphate.  In  both  the  rabbit  and  the  dog  the 
amido-phenols  are  also  eliminated  as  sulphates.  In  man,  the  acetyl-group 
is  not  wholly  oxidised,  the  urine  containing  the  sulphate  of  aceto-par- 
a  m  i  d  0  p  h  e  n  o  1.  In  all  cases  there  is  an  oxidation  of  one  of  the  hydrogen 
atoms  of  the  benzene-nucleus  to  hydroxyl,  while  the  proportion  of  ethereal 
sulphates  is  increased  (compare  "Aniline,"  page  46),  the  urine  is  red  from 
excess  of  bilirubin,  reduces  alkaline  cupric  solution,  and  is  strongly  laevo- 
rotatory  ;  the  optically  active  body  probably  being  the  above-mentioned 
sulphate  (Gressly  and  Nencki,  Monatsh.,  xi.  253). 


72  EXALGIN.      BENZANILIDE. 

of  J  to  4  grains  its  effects  are  said  to  be  very  satisfactory.  Exalgin 
forms  fine  needles  or  large  white  tablets  (compare  "Acetanilide"). 
It  melts  at  100°-101°,  boils  without  decomposition  between  240° 
and  250°,  and  is  slightly  soluble  in  cold  water,  but  more  so  in 
boiling,  and  very  soluble  in  water  containing  a  little  alcohol.  It 
is  saponified  with  difficulty  by  caustic  alkali,  but  completely  by 
concentrated  hydrochloric  acid,  with  formation  of  acetic  acid  and 
methylaniline. 

Hirschsohn  states  that  exalgin  may  be  distinguished  from 
antifebrin  and  phenacetin  by  treating  1  gramme  with  2  c.c.  of 
chloroform,  which  dissolves  the  exalgin  only.  A  chloroformic 
solution  of  exalgin  remains  clear  on  adding  ten  measures  of 
petroleum  ether,  whereas  the  solutions  of  antifebrin  and  phenacetin 
become  turbid.  20  per  cent,  of  acetanilide,  or  10  of  phenacetin, 
may  be  detected  in  exalgin  by  these  reactions.  An  aqueous  solution 
of  antifebrin  gives  a  bromo-derivative  on  adding  bromine-water, 
thus  differing  from  exalgin  and  phenacetin.^ 

Benzanilide,  CgH^.NH(C0.CgH5),  is  obtained  by  the  action  of 
benzoyl  chloride  on  aniline,  or  by  boiling  together  equivalent 
quantities  of  benzoic  acid  and  aniline.  It  forms  a  white,  crystalline 
powder,  melting  at  160°-161°  and  volatile  without  decomposition. 
It  is  almost  insoluble  in  water,  but  dissolves  in  fifty-eight  parts  of 
cold,  or  seven  of  boiling,  alcohol,  crystallising  on  cooling  in  nacreous 
plates.  It  is  difficultly  soluble  in  ether.  Benzanilide  is  not 
attacked  by  aqueous  alkalies  or  acids,  but  is  saponified  by  fusion 
with  caustic  potash.  It  has  been  found  valuable  as  an  antipyretic 
for  children,  in  doses  of  2  to  8  grains,  and  is  said  not  to  produce 
objectionable  secondary  effects. 

Phenyl-urethane.  Ethyl  Carbanilate.  CgHg.NHfCO.OCgHg). 
This  compound  has  recently  acquired  a  practical  interest  owing 
to  its  introduction  as  a  synthetic  remedy  under  the  name  of 
"  e  u  p  h  0  r  i  n."  It  is  produced  by  the  reaction  of  aniline  on  ethyl- 
chlorocarbonate,  and  occurs  as  a  white  crystalline  powder,  of  a  faintly 
aromatic  odour  and  scarcely  perceptible  taste,  which  subsequently  be- 
comes acrid  and  clove-like.  It  melts  at  49°  to  51°,  boils  at  237°, 
and  is  only  slightly  soluble  in  cold  water,  but  very  freely  soluble  in 
alcohol,  and  sufficiently  soluble  in  sherry  and  other  alcoholic  liquids 
to  be  conveniently  given  in  solution  in  such  menstrua.     According 

^  Exalgin  may  also  be  distinguished  from  antifebrin,  methacetin,  and  phen- 
acetin by  treating  2  grains  (or  0*1  gramme)  with  20  minims  (or  1  c.c.)  of 
concentrated  hydrochloric  acid.  Phenacetin  remains  insoluble.  Antifebrin 
dissolves,  but  separates  again  in  crystals  of  the  hydrochloride.  Methacetin 
also  dissolves,  but  is  recognised  by  the  reddish-brown  coloration  produced  on 
adding  one  drop  of  nitric  acid. 


SUBSTITUTED   ANILINES. 


73 


toSansoni,  after  administration  of  phenyl- ure thane,  the  urine 
shows  the  para-amidophenol  reaction  either  directly  or  after  dis- 
tillation with  potassium  carbonate.  The  proportion  of  urea  is 
increased,  but  the  urine  is  free  from  phenol,  aniline,  albumin,  and 
sugar. 

Substituted  or  Alkylated  Anilines. 

These  bases  result  from  the  replacement  of  one  or  both  of  the 
hydrogen  atoms  of  the  amido-group  of  aniline  by  alkyl  or  other 
basylous  radicals. 

The  bases  of  this  class  are  obtained  by  heating  the  hydro- 
chloride or  other  salt  of  aniline  (or  its  homologues)  with  the 
alcohol  with  which  it  is  intended  to  react,  or  the  halogen  salt  of 
this  alcohol  with  free  aniline. 

The  only  substituted  anilines  which  require  special  description 
are  the  following  : — 


Formula. 

Specific 
Gravity. 

1 
Boiling- Point:    Reference. 

Methyl-aniline,     .     .     . 
Dimethyl-aniline,      .     . 
Ethyl-aniline,  .... 
Diethyl-aniline,    .     .     . 
Phenyl-aniline 

(Diphenylaraine),    . 
Diphenyl-auiline 

(Triphenylamine),    . 

C6H5.NH(CH3) 

r6H5.N(CH3)2 

CeHg.NHCCsHg) 

C6H5.N(C2H5)2 

CeHg-NHCCeHe) 

C6H5.N(C6H6)2 

•976   at  15* 
•9553  at  15' 
•954    at  18° 
•937    at  13° 

1161 

192 
192 
204 
213  ^5 

302 

Page  73. 
Page  74. 

Page  79. 

Page  79. 

Page  80. 

Diphenylamine  is  a  very  weak  base,  and  in  triphenylamine  the 
basic  character  is  entirely  lost. 

Methyl-aniline.     CgH5.NH(CH3). 

This  base  is  obtained  by  the  action  of  iodide,  nitrate,  or  chloride 
of  methyl  on  aniline,  or  by  heating  methyl  alcohol  with  aniline 
hydrochloride.^  In  all  cases  dimethyl-aniline  is  formed  simultane- 
ously, and  hence  in  the  production  of  mono-methylaniline  a  portion 
of  the  aniline  remains,  in  practice,  unattacked.^ 

^  Pure  methylaniline  may  be  obtained  by  the  reaction  of  methyl  iodide  ot 
sodium  acetanilide,  C6H5.NNa(C2H30),  and  saponification  of  the  re- 
sultant compound  l>y  caustic  alkali. 

^  To  separate  this  from  its  mono-  and  di-methyl-derivatives,  dilute  sulphuric 
acid  is  added  as  long  as  aniline  sulphate  continues  to  separate.  The  sulphuric 
acid  solution  is  separated  from  the  solid  aniline  sulphate  by  pressure  in  a 
linen  cloth,  and  the  expressed  liquid  treated  with  caustic  soda.  The  substance 
which  separates  is  dried  and  treated  with  acetyl  chloride  until  no  further 
rise  of  temperature  is  observed,  when  the  product  is  poured  into  cold  water. 
On  cooling,  methyl-acetanilide,  C6H5.N(CH3)(C.^H30),  separates  in  long 
needles,  while  dimethylaniline  hydrochloride  remains  in  solution. 


74  METHYL-ANILINE. 

Methylaniline  is  a  liquid  boiling  at  192"*.  It  resembles  aniline, 
but  is  ligliter  than  water,  and  its  odour  is  stronger  and  more 
aromatic.  The  sulphate  is  soluble  in  ether  and  uncrystallisable. 
A  solution  of  bleaching  powder  first  colours  it  violet  and  then 
brown.  The  conversion  of  methylaniline  into  toluidine  is  re- 
ferred to  on  page  41. 

Methf/IaniUne-nitrosamine,  CgH5.N(CH3)(NO),  separates  as  a 
yellow  oil  on  treating  a  cold  solution  of  methylaniline  hydro- 
chloride with  sodium  nitrite,  while  any  aniline  and  dimethyl- 
aniline  are  converted  into  soluble  products.  If  the  nitrosamine 
be  extracted  by  ether,  and  treated  with  tin  and  hydrochloric 
acid,  it  is  reduced  to  methylaniline,  which  may  thus  be  obtained 
in  a  pure  state  (compare  page  7).  The  nitrosamine  is  destitute 
of  basic  properties.  It  has  an  aromatic  odour,  and  may  be 
distilled  in  a  current  of  steam,  but  not  alone.  When  methyl- 
aniline-nitrosamine  is  warmed  with  phenol  and  sulphuric  acid, 
the  mixture  diluted  with  water  and  saturated  with  caustic 
alkali,  it  yields  the  intense  green-blue  coloration  produced  by 
all  nitrosamines  (L  i  e  b  e  r  m  a  n  n's  reaction).  When  heated  with 
alcoholic  hydrochloric  acid  it  undergoes  molecular  transformation 
into  para nitroso- methylaniline,  CgH4(N"0).NH(CH3),  a 
body  crystallises  in  green-plates  or  steel-blue  prisms,  and  other- 
wise resembling  paranitroso-dimethylaniline  (page  75). 

Dimethyl-aniline.     CgH5.N(CH3)2. 

This  important  base  is  obtained  by  the  action  of  excess  of  methyl 
iodide  on  aniline.  On  the  large  scale,  methyl  iodide  was  formerly 
employed,  but  was  afterwards  replaced  by  the  nitrate,  and  this 
again  (owing  to  its  explosive  properties)  was  superseded  by  the 
very  volatile  methyl  chloride.  The  product  obtained  in  this  way 
contained  about  5  per  cent,  of  monomethyl-aniline,  but  no  other 
admixtures.  Dimethylaniline  is  now  always  manufactured  by 
heating  together  a  mixture  of  aniline  hydrochloride,  aniline,  and 
methyl  alcohol.^     The   methyl   alcohol   employed   must   be   quite 

The  former  product  is  saponified  by  boiling  with  dilute  hydrochloric  acid, 
which  converts  it  into  acetic  acid  and  methyl-aniline  hydrochloride.  Another 
method  of  separating  aniline  from  its  mono-  and  di-methyl-derivatives  is 
referred  to  in  the  footnote  on  page  76.  Methyl-aniline  can  be  re-formed  by 
treating  its  nitroso-derivatives  with  tin  and  hydrochloric  acid. 

^  The  aniline  must  be  free  from  toluidine  and  impurities  insoluble  iu 
hj'drochloric  acid ;  and  the  methyl  alcohol  employed  must  be  quite  fiee 
from  ethyl  alcohol  and  acetone,  the  latter  of  which  not  only  reduces  tlie 
yield,  but  gives  a  product  unsuitable  for  the  preparation  either  of  methyl 
violet  or  malachite  green,  owing  to  the  formation  of  a  base  of  the  formula 
CH2(CeH4.N(CH3)2)2.     93  parts  of  aniline  are  used,  of  which  18  are  saturated 


DIMETHYL-ANILINE.  76 

free  from  etliyl  alcohol  and  acetone,  the  latter  of  which  not  only 
reduces  the  yield,  but  gives  a  product  unsuitable  for  the  prepara- 
tion either  of  methyl-violet  or  malachite-green,  owing  to  the  forma- 
tion of  a  base  of  the  formula  : — CH2(CgH4.N(CH3)2)2. 

Dimethylaniline  is  a  colourless  oily  liquid,  solidifying  at  0°"5 
and  boiling  at  192°.  It  has  a  sharp  basic  odour,  and  forms 
uncrystallisable  salts.  It  unites  with  methyl  iodide,  with  energy 
at  the  ordinary  temperature,  to  form  the  iodide  of  trimethyl- 
phenylammonium,  which  breaks  up  again  into  its  constituents 
on  distillation,  but  by  reaction  with  argentic  oxide  yields  tri- 
methyl-phenyl-ammonium  hydroxide,  MegPhN.OH,  a 
crystalline,  very  deliquescent,  corrosive,  and  very  bitter  base. 

With  bleaching-powder  solution,  dimethylaniline  merely  gives 
a  pale  yellow  coloration,  a  reaction  by  which  any  contamination 
by  aniline  or  mono-methylaniline  can  be  detected,  as  these 
bases  give  a  violet  colour  with  the  same  reagent  (page  45). 
Mild  oxidising  agents,  such  as  chloranile,  carbon  oxychloride, 
and  cupric  chloride,  convert  the  methylaniline  into  methyl  violet 
(Part  I.  page  234).  With  acid  chlorides  and  aldehydes,  it  yields 
complex  compounds.  Thus  with  benzaldehyde  it  gives  tetra- 
methyl-paradiamido-triphenylmethane,  and  the 
corresponding  hydroxide  or  carbinol,  CgH5.[N(CH3)2]2.0H, 
obtained  from  this  by  oxidation,  is  the  base  of  malachite  or  benz- 
aldehyde green  (Part  I.  page  241).  By  reaction  with  diazobenzene 
chloride,  dimethylaniline  is  converted  into  dim e th y  1-amid o- 
azobenzene,  CgH5.N2.CeH4.N(CH3)2,  or  butter  yellow;  while  with 
diazobenzene-sulphonic  acid  it  yields  helianihin  or  methyl-orange 
(Part  I.  page  188). 

Paranitroso-dimethylaniline,  C^J^0).^{(yR^2^  is  produced  by 
the  action  of  nitrite  of  sodium  or  nitrite  of  amyl  on  dimethyl- 
aniline.^    It  is  manufactured  on  a  large  scale  for  the  production 

with  hydrochloric  acid  and  75  parts  of  methyl  alcohol.  The  excess  of 
methyl  alcohol,  and  comparatively  small  quantity  of  hydrochloric  acid,  tend  to 
produce  a  purer  oil.  With  more  hydrochloric  acid,  the  reaction  takes  place 
at  a  lower  temperature,  but  there  is  a  danger  of  forming  toluidine.  The 
mixture  is  lieated  at  first  to  a  temperature  of  270°,  at  a  pressure  not  exceeding 
27  atmospheres.  When  the  reaction  is  complete,  in  about  15  hours,  the 
pressure  decreases  without  the  temperature  being  reduced  (Schoop,  Chem. 
Zeit.,  xi.  253  ;  Jour.  Soc.  Chem.  Ind.,  vi.  436). 

^  Ten  parts  of  dimethyl-aniline  are  dissolved  in  50  of  strong  hydrochloric 
acid  and  200  of  water,  and  to  the  cold  solution  is  gradually  added  a  solution 
of  5*7  parts  of  sodium  nitrite  in  200  of  water,  when  the  hydrochloride  of 
the  nitroso-compound  is  obtained  as  a  body  crystallising  in  yellow  needles, 
from  which  the  free  base  is  obtained  by  treatment  with  potassium  carbonate 
and  solution  in  ether. 


76  NITROSO-DIMETHYL-ANILINE. 

of  methylene-blue,  indophenol,  and  toluylme-red  (Part  I.  pages 
258,  285).  It  crystallises  in  large  green  plates  or  tables,  soluble 
in  ether.  By  oxidation  with  potassium  permanganate  or  ferri- 
cyanide,  it  is  converted  into  paranitro-dimethylaniline, 
CgH4(N02).N(CH3)2,  which  forms  long,  sulphur-yellow  needles, 
melting  at  162°-163°.  When  boiled  with  caustic  alkali,  nitroso- 
dimethylaniline  is  completely  split  up  into  dimethylamine, 
H.N(CH3)2  (which  may,  by  this  reaction,  readily  be  obtained 
pure), and  nitrosophenol  or  quinonoxime,  CgH^O(NOH) 
(Part  I.  page  157). 

Commercial  Dimetliylaniline  usually  contains  more  or  less 
aniline  and  monomethyl-aniline.  By  the  entrance  of 
methyl  into  the  benzene-nucleus,  more  or  less  dimethyl- 
1 0 1  u  i  d  i  n  e,  CgH4(CH3).  N(CH3)2,  and  higher  homologues  are 
usually  present  in  addition.  Hence  the  dimetliylaniline  of  com- 
merce usually  boils  between  198°  and  205°.  The  smaller  the 
range  in  the  boiling-point  the  better  the  sample. 

The  presence  of  aniline  and  monomethyl-aniline  is  indicated  by 
the  rise  of  temperature  produced  on  treating  5  c.c.  of  the  dry  oil 
with  an  equal  measure  of  acetic  anhydride.  This  is  stated  to  be 
0°'815  C.  for  each  unit  per  cent,  of  monomethylamine  present. 
For  small  percentages  this  appears  to  be  fairly  correct,  but  with  a 
product  actually  containing  30  per  cent.,  an  excess  of  over  7  per 
cent,  is  said  to  be  indicated.  A  serious  objection  to  the  method  is 
that  it  wholly  fails  in  presence  of  aniline.  But  the  presence  of 
aniline  can  be  recognised  by  mixing  a  few  drops  of  the  oil  with  a 
few  drops  of  ether,  and  adding  one  drop  of  strong  sulphuric  acid, 
when,  if  aniline  be  present,  its  sulphate  will  separate  as  a  white 
precipitate. 

A  more  plausible  method  is  that  of  Nolting  and  B o a s s o n 
{Ber.,  X.  795),  based  on  the  different  behaviour  of  the  bases  with 
nitrous  acid,^  but  the  results  yielded  in  practice  have  been  found 

^  When  aniline  hydrochloride  is  treated  in  cold  solution  with  sodium  nitrite, 
it  yields  diazobenzene  chloride,  while  dimetliylaniline  is  converted  into 
the  hydrochloride  of  its  nitroso-derivative  (pap:e  75).  Both  these  bodies  are 
freely  soluble  in  water,  while  monomethyl-aniline  is  converted  by  the  same 
treatment  into  the  non-basic  methylaniline-nitrosamine,  which 
can  be  extracted  by  agitating  the  liquid  with  ether.  If  this  reaction  occurred 
in  its  simplicity,  the  monomethyl-aniline  could  be  estimated  from  the  weight 
of  the  nitrosamine  left  on  evaporating  the  ethereal  solution.  But  when 
this  is  distilled  in  a  current  of  steam,  in  which  the  nitrosamine  is  vola- 
tile, a  considerable  quantity  of  nitrophenyl-methylnitrosamine, 
C6H4(N02).N(NO)(CH3),  remains  as  a  residue.  This  body  is  clearly  produced 
by  the  oxidation  of  the  nitrosamine,  and  direct  experiment  shows  that  pure 
monomethyl-aniline,  on  treatment  with  excess  of  nitrous  acid,  is  converted 


ASSAY   OF  DIMETUVL- ANILINE.  77 

unreliable  by  R  e  v  e  r  d  i  n  and  de  la  Harpe.  These  chemists 
recommend  {Cliem.  Zeit.,  xiii.  387,  407  ;  Jour.  Soc.  Chem.  Ind.^ 
viii.  84),  for  the  estimation  of  thrj  aniline  and  methyl-aniline  con- 
jointly, acetylisation  of  the  bases,  and  estimation  of  the  excess  of 
acetic  anhydride  by  titration  with  alkali ;  and  for  the  estimation  of 
the  aniline,  diazotising  and  treating  the  product  with  beta-naphthol 
disulphonic  acid. 

At  ordinary  temperatures  acetic  anhydride  has  no  action  on 
dimethylaniline,  but  on  prolonged  heating  tetramethyl- 
diamido-phenylmethaneis  formed  in  considerable  quantity, 
if  the  reagent  be  in  excess.  Monomethyl-aniline  is  converted  into 
methyl-acetanilide,  CgH5.N(CH3)(C2H30),  and  aniline  in 
the  cold  yields  acetanilide,  CgH^.NHCgHgO,  but  on  heating 
more  or  less  diacetanilide,  CgH5.N(C2H30)2,  is  produced. 
To  avoid  the  formation  of  these  secondary  products  the  following 
method  of  working  is  recommended : — From  1  to  2  grammes 
weight  of  the  sample  is  mixed  as  rapidly  as  possible  with  an  accur- 
ately known  quantity  (about  twice  its  weight)  of  acetic  anhydride, 
in  a  small  flask  fitted  with  a  reflux  condenser.  After  standing 
for  half  an  hour  at  the  ordinary  temperature,  50  c.c.  of  water 
should  be  added,  and  the  flask  heated  on  the  water-bath  for  fifty 
minutes  to  efl'ect  the  conversion  of  the  excess  of  acetic  anhydride 
into  acetic  acid.  The  liquid  is  then  cooled,  diluted  to  a  known 
volume,  and  an  aliquot  part  titrated  with  standard  caustic  alkali, 
using  phenolphthalein  as  an  indicator.^  By  this  means  the  excess 
of  acetic  anhydride,  C^HgOg,  is  ascertained,  and  the  diff'erence 
between  the  amount  so  found  and  that  employed  is  the  weight 
which  has  reacted  with  the  aniline  and  methyl-aniline  contained  in 
the  sample.  5 1  parts  of  acetic  anhydride  consumed  in  the  reaction 
correspond  to  107  of  base  in  terms  of  methyl-aniline^  and  the  per- 
centage of  base  thus  found  (a)  is  calculated  and  recorded. 

The  aniline  itself  is  determined  as  follows : — From  7  to  8 
grammes  of  the  sample  is  dissolved  in  hydrochloric  acid  (28  to  30 
c.c),  and  diluted  with  water  to  100  c.c.      10  c.c.  of  this  solution 

into  it,  to  the  exclusion  of  the  simple  nitrosamine.  As  the  molecular  weights 
of  the  two  bodies  are  materially  different  (181  :  136),  the  indefinite  character  of 
the  reaction  prevents  the  accurate  determination  of  the  monomethylamine 
(Reverdin  and  de  la  Harpe,  Chem.  Zeit.,  xiii.  387,  407;  Jour.  Soc. 
Chem.  Ind.,  viii.  84). 

1  H.  Giraud  {Bull.  Soc.  Chim.,  1889,  ii.  142)  modifies  this  process  by 
employing  the  acetic  anhydride  dissolved  in  ten  times  its  vohime  of  dimethyl- 
aniline.  10  c.c.  of  this  solution  is  added  to  1  gramme  of  the  sample.  After 
standing  for  one  hour  in  a  corked  flask,  water  is  added,  and  the  liquid  (boiled 
for  some  time  and)  titrated  with  standard  baryta- water  or  phenolphthalein. 


78  ASSAY   OF   DIMETHYL- ANILINE. 

is  further  diluted  with  water  and  cooled  by  ice.  The  solution  is  then 
diazotised  by  adding  a  solution  of  sodium  nitrite  in  quantity  suffi- 
cient to  react  with  the  whole  of  the  sample  if  it  consisted  of  aniline 
solely.  A  solution  of  the  sodium  salt  of  betanaphthol-disulphonic 
acid  known  as  "Salt  R"  (Part  I.  page  194)  is  meanwhile  prepared  of 
a  strength  approximately  corresponding  to  10  grammes  of  naphthol 
per  litre,  and  its  precipitating  power  is  calculated  from  its  known 
strength,  or  exactly  ascertained  by  experiment  with  pure  aniline. 

A  measured  quantity  of  this  solution  is  then  treated  with  ex- 
cess of  sodium  carbonate,  and  to  it  the  ice-cold  solution  of  the 
diazotised  sample  is  slowly  added.  Common  salt  is  then  added 
till  a  precipitate  ceases  to  form,  when  the  liquid  is  filtered,  and 
portions  of  the  filtrate  are  tested  with  salt  R  and  the  diazo- 
solution  respectively,  to  ascertain  which  of  these  two  is  present  in 
excess.  Another  experiment  is  then  made  with  suitably  varied 
volumes,  until  after  a  few  trials  exact  precipitation  of  the  colouring 
matter  is  attained  without  sensible  excess  of  either  the  naphthol 
or  diazo-solution.     The  reactions  which  occur  are  as  follow  : — 

C6H5.NH2,HCl4-  HN02  =  C6H5N  :  N.CI  +  2H2O  ;  and 
C6H5.N2.CI  +  CioH,(OH)(S03Na)2  =  HCl  +  CeH5.N2.CioH,(OH)(S03Na)2 . 

From  these  formulae,  and  the  volumes  of  the  two  solutions  required 
for  exact  reaction,  the  weight  of  aniline  present  can  be  calculated. 
1  gramme  of  salt  R  will  react  with  0'2672  gramme  of  aniline. 
The  percentage  of  aniline  thus  found  {h)  is  multiplied  by  1*15 
(  =  ^),  which  gives  its  equivalent  in  methyl-aniline,  and  this  (c) 
subtracted  from  the  sum  of  aniline  and  methyl-aniline  in  terms  of 
methyl-aniline  found  by  the  acetylisation  process  {a)  gives  the  per- 
centage of  real  methyl-aniline  (d)  present.  The  dimethyl-aniline  is 
determined  by  difference. 

In  the  case  of  a  sample  of  known  composition.  R  e  v  e  r  d  i  n 
and  de  la  Harpe  obtained  the  following  satisfactory  results 
by  the  foregoing  process  : — 

Present.  Found. 

Aniline,         .         .  10"42  per  cent.  10  30  per  cent. 

Monomethylaniline,  10*97        „  11*16        „ 
Dimethylaniline  (by 

difference),         .  78*61        „  78*54 


100*00        „  10000       „ 

The  presence  of  monomethylaniline  is  more  objectionable  in  dia- 
raethylaniline  intended  for  the  manufacture  of  green  than  in  that 
to  be  used  for  violet.     S  c  h  0  0  p  (Chem.  Zeit.^  xi..  254)  states  that 


DIPHENYLAMINE.  79 

the  proportion  seldom  exceeds  2  per  cent.,  and  that  the  best 
qualities  of  dimethylaniline  are  nearly  6r  quite  free  from  it.  AYhen 
[)resent,  monomethylaniline  can  be  removed  by  shaking  the  oil  with 
a  small  quantity  of  dilute  sulphuric  acid,  or  by  boiling  with  acetic 
acid  for  two  hours. 

DiETHYLANILINE.       CeH5.N(C2H5)2. 

This  base  is  best  prepared  by  heating  one  molecule  of  aniline 
hydrobromide  with  10  per  cent,  in  excess  of  one  molecule  of  ethyl 
alcohol  to  145°  for  8  or  10  hours.  Nearly  the  theoretical  yield  is 
obtained.  The  base  boils  at  21 3°-5.  Diethyl-orthotoluidine  and 
diethyl-paratoluidine  may  be  obtained  by  exactly  similar  means. 

DiPHENYLAMINE.       PhENYLANILINE.       C6H5.NH.C6H5. 

This  base  is  obtained  by  heating  aniline  with  the  hydrochloride 
or  other  salt  of  aniline.^  Diphenylamine  crystallises  in  small  white 
plates,  having  an  agreeable  flowery  odour  and  burning  taste.  It 
melts  at  54°,  and  boils  at  302°  C.  (Graebe).  It  is  almost  insoluble 
in  water,  but  readily  in  alcohol,  ether, benzene, and  aniline.  Diphenyl- 
amine has  very  feeble  basic  properties.  The  hydrochloride  is  a  white 
crystalline  powder,  which  turns  blue  in  the  air,  and  is  decomposed 
by  water.  The  most  characteristic  reaction  of  diphenylamine  is  the 
deep  blue  colour  produced  by  adding  a  trace  of  nitric  acid  to  its 
solution  in  strong  sulphuric  acid.  The  reaction,  which  is  very 
delicate,  is  employed  as  a  test  for  nitric  acid. 

Commercial  diphenylamine  should  be  pale  yellow,  melt  not 
much  below  54°,  be  free  from  unpleasant  odour  and  oily  matters, 
and  give  no  violet  coloration  with  bleaching  powder.  It  is  used 
for  making  diphenylamine  Uue,  aurantia,  and  orange  IV. 

Methijl-diphenylamine,  CqR^.1<^(CR^)CqH^,^  boils  at  282°,  and 
gives  various  colour-reactions  with  oxidising  agents.  In  dilute  sul- 
phuric acid  it  dissolves  to  form  a  liquid  of  the  colour  of  solution  of 
potassium  permanganate. 

^  Six  parts  of  aniline  and  7  of  anilino  hydrochloride  are  heated  to  250" 
untler  a  pressure  of  4  or  5  atmospheres  for  24  hours.  The  ammonia  formed  is 
allowed  to  escape  at  intervals  to  prevent  reconversion  of  the  diphenylamine 
into  aniline.  The  product  is  treated  with  warm  hydrochloric  acid  and  a  large 
quantity  of  water,  which  dissolves  any  unchanged  aniline  hydrochloride,  and 
decomposes  the  hydrochloride  of  diphenylamine,  which  latter  base  separates 
out  and  is  purified  by  distillation. 

^  Made  on  a  large  scale  by  heating  a  mixture  of  100  parts  of  diphenylamine, 
68  of  hydrochloric  acid  (sp.  gr.  1"17),  and  2  parts  of  methyl  alcohol  for  10 
hours,  to  200''-250''  at  a  pressure  of  15  atmospheres.  The  product  is  treated 
with  caustic  soda,  and  the  separated  base  distilled  and  shaken  with  twice  its 
measure  of  strong  hydrochloric  acid.  The  hydrochloride  of  diphenylamine 
separates  in  the  solid  form,  while  that  of  the  methyl-derivative  forms  a  liquid, 
which  is  decomposed  by  adding  a  large  quantity  of  water. 


80  AMIDOPHENOLS. 

Warm  nitric  acid  converts  diphenylamine  and  its  methyl- 
derivative  into  CgH2(N02)3.ISrH.C(.H2(N02)3 ,  hexanitro-di- 
phenylamine,  the  ammonium  salt  of  which  constitutes  the 
colouring  matter  known  as  aurantia  (Part  I.  page  156). 

Para-amidu-diphenylamine  results  from  the  reduction  of  phenyl- 
amido-azobenzene,  nitro-phenylamine,  or  tropceoUn  00  (Part  I. 
pages  181,  189,  190,  213). 

Triphenylamine.     Diphenylaniline.     (C6H5)3N. 

This  body  is  formed  by  the  action  of  bromobenzene  on  dipotas- 
sium  aniline.  It  is  a  neutral  body,  melting  at  127°,  and  crystallising 
from  ether  in  nionoclinic  pyramids.  It  forms  no  isonitrile,  picrate, 
nor  acetyl-compound,  but  yields  iodide  of  triphenyl-m ethyl-am- 
monium on  treatment  with  methyl  iodide.  Its  solution  in  glacial 
acetic  acid  is  coloured  green  on  adding  a  little  nitric  acid,  but  with 
sulphuric  acid  it  gives  a  violet  coloration  changing  to  blue. 

AmicLophenols. 

By  the  reduction  of  the  nitrophenols,  corresponding  amido- 
compounds  are  obtained.  These  bodies  may  also  be  prepared  by 
heating  either  of  the  three  isomeric  amido-hydroxybenzoic  acids, 
C6H3(NH2)OH.COOII,  with  caustic  baryta. 

In  the  amidophenols  the  acid  character  of  the  phenols  is  neutral- 
ised by  the  presence  of  the  amido-groups,  so  that  they  only  yield 
salts  with  acids ;  but  as  phenols  they  are  still  capable  of  yielding 
alkyl-derivatives  (e.p'.,  anisidine),  while  the  hydrogen  of  their 
amido-groups  may  be  replaced  for  acetyl, &c.,  as  in  phenacetin 

The  amidophenols  form  colourless  crystalline  scales  or  plates, 
which  are  very  readily  oxidisable  on  exposure  to  air,  with 
blackening  and  formation  of  resinous  products,  especially  if 
impure.  On  the  other  hand,  their  hydrochlorides  are 
relatively  stable,  and  often  capable  of  sublimation.  The  solution 
of  para  mid  ophenol  hydrochloride  is  coloured  first  violet  and  then 
green  by  solution  of  bleaching  powder,  quinone  chlorimide, 
C6ll40(NCl),  being  formed ;  while  with  chromic  acid  mixture, 
and  other  oxidising  agents,  it  yields  quinone,  CgH^Og.  Treat- 
ment with  sulphuretted  hydrogen  and  ferric  chloride  converts 
it  into  compounds  of  the  methylene-hlue  group  (Part  I,  page  285). 

The  formyl-  and  acetyl-derivatives  of  the  amidophenols  are 
converted  with  great  facility  into  anhydro-bases.  Thus  e  t  h  e  n  y  1- 
amidophenol,  a  basic  liquid  boiling  at  200°  to  201°,  is 
obtained  by  boiling  ortho-amidophenol  with  acetic  anhydride. 

C6H,(OH).NHC2H30  =  C^B./   ^C.CHg + Kfi. 


AMIDO-PHENOLS. 


81 


When  this  body  is  heated  with  dilute  acids,  the  reverse  action 
occurs,  acetyl-orthoamidophenol  being  formed. 

The  methyl  esters  of  the  amidophenols  (anisidines  or 
amido-anisols),  and  the  corresponding  ethyl  esters  (phenethi- 
dines  or  amidophenatols),  are  bases  resembling  aniline,  and  are 
employed  for  producing  certain  azo-dyes  (e.g.,  anisol  red,  phenatol 
red;  Part  I.  page  192).  The  acety  1-deri vati ves  of  these 
esters  are  used  in  medicine  under  the  names  of  metacetin  and 
phenacetin  (see  below). 

The  following  table  shows  the  characters  of  the  isomeric  amido- 
phenols and  their  derivatives  : — 


1 

OrtHO-  1 : 2 

META-  1 : 3 

PARA-  1 : 4 

tl 

ii 

ft 

ii 

fi 

Amidophenol  (page  80), 

170 

sub- 
limes. 

... 

... 

184 

... 

Acetyl-derivative  (page  80),  ... 
^6^nNH(COCH3) 

201 

... 

... 

... 

179 

... 

Methyl-ester  (Anisidine) 

p  „   rOCCHs) 
C6H4|nH2 

•• 

228 

... 

251 

56 

246 

Ethyl-ester  (Phenethidine),    .... 

229 

... 

180-205 
(at  100 
mm.) 

... 

253 

Methacetin  (page  85),     .       .       .       . 
C6^4{n*S(COCH3) 

84 

204 

... 

... 

127 

... 

Phenacetin  (page  81), 

70 

97 

... 

135 

... 

Amidophenacetin.    Phenocoll  (page  85),     . 
C6H4{g^§?6)cH,NH,) 

... 

... 

... 

... 

100-5 

Phbnacbtins. 


ACET-PHBNBTHIDINBS. 

an. 


1 1  occ^H,) 

^*tNH(C0.CH3) 


The  bodies  of  this  formula  have  recently  acquired  some  reputa- 
tion as  antipyretics  and  analgesics. 

The  phenacetins  are  prepared  by  ethylating  the  corresponding 
mono-nitrophenols,  thus  obtaining  the  isomers  of  the  formula 
C6H^(N02).OC2H5.     On  treatment  with  zinc  or  iron  and  hydro- 

VOL.  III.  PAKT  II.  F 


82  ACET-PHENETHIDINES. 

chloric  acid,  these  are  reduced  to  the  corresponding  phen- 
ethidines,  CgH4(NH2).OC2H5,  which  are  purified  and  acetylised 
by  heating  with  glacial  acetic  acid  for  some  hours,  the  products 
being  recrytallised  from  water. 

Of  the  three  isomeric  phenacetins,  the  mefa-compound  is  unim- 
portant.    It  forms  tasteless  and  odourless  scales,  melting  at  96°. 

Para-acetphenethidine  is  the  official  variety  in  the  German  and 
British  Pharmacopoeias  (1890).  It  forms  white,  odourless,  taste- 
less, glistening  scaly  crystals.  It  requires  1400  parts  of  cold,  or 
70  parts  of  boiling,  water  for  solution,  and  is  soluble  to  a  notable 
extent  in  chloroform.  Its  solution  in  1 6  parts  of  alcohol  is  precipi- 
tated by  the  smallest  addition  of  water.     The  crystals  melt  at  135°. 

Ortho-acetphenethidine  forms  brilliant  white,  very  light  spangles, 
without  taste  or  odour,  and  melting  at  70°  C.  It  is  very  slightly 
soluble  in  cold,  but  more  readily  in  hot,  water,  separating  again  on 
cooling.  It  dissolves  in  about  three  parts  of  rectified  spirit,  and 
abundantly  in  chloroform. 

Besides  the  difi'erences  in  their  melting-points  and  solubilities, 
para-  and  ortho-phenacetin  are  distinguished  by  their  behaviour 
when  boiled  for  several  hours  with  dilute  sulphuric  acid  (sp.  gr. 
1*26).  When  thus  treated,  the  para- compound  yields  acetic  acid 
and  sparingly  soluble  sulphate  of  phenethidine.  Orthophenacetin, 
on  the  other  hand,  is  not  decomposed  by  the  same  treatment,  re- 
quiring the  action  of  acid  of  1*575  specific  gravity  for  two  hours  at 
90°  to  effect  its  saponification.^  If  in  either  case  the  acid  liquid 
be  diazotised,  and  then  treated  with  an  ammoniacal  solution  of 
naphthol-disulphonic  acid,  a  fine  red-yellow  colour  will  be  obtained 
if  paraphenacetin  was  employed,  while  with  the  ortho-compound 
a  cherry-red  coloration  is  produced.  In  either  case  the  colouring 
matter  may  be  precipitated  by  brine. 

This  formation  of  an  azo-colouring  matter  may  be  employed  to 
detect  the  phenacetins  in  urine  and  other  organic  liquids.  The 
urine  is  evaporated  to  dryness,  and  the  residue  treated  with  hot 
alcohol.  The  solution  is  filtered,  evaporated,  and  the  residue  boiled 
for  two  hours  with  dilute  sulphuric  acid  (sp.  gr.  1'26)  under  a 
reflux  condenser.  The  resultant  solution  is  cooled  to  5°  or  6°  C, 
treated  with  a  1  per  cent,  solution  of  sodium  nitrite  for  five 
minutes,  and  then  poured  into  a  solution  of  napthol-disulphonic 
acid  in  excess  of  ammonia,  taking  care  that  the  mixture  remains 

^  S.  Liittke  detects  orthophenacetin  by  boiling  15  grammes  of  the  sample 
with  25  grammes  of  dilute  hydrochloric  acid,  when  ortho-phenethidine  hydro- 
chloride is  formed,  from  which  the  free  base  may  be  separated  by  caustic  soda, 
and  its  boiling-point  (given  by  Liittke  as  242° '5)  determined.  The  hydro- 
chloride gives  a  blood-red  coloration  with  ferric  chloride. 


PHENACETIN.  83 

alkaline.  If  either  modification  of  phenacetin  be  present  in  the 
urine  a  characteristic  coloration  will  be  produced,  from  the  intensity 
of  which  the  amount  of  phenacetin  may  be  estimated. 

For  medicinal  use,  phenacetin  is  said  to  present  considerable 
advantages  over  antipyrine,  and  especially  over  antifebrin  (acet- 
anilide),  for  while  the  latter  body  is  decomposed  in  the  system 
with  formation  of  aniline,  which  has  marked  toxic  properties, 
phenacetin  yields  phenethidine,  CqKJ^OC2'S.^).^'H.2,  and 
amidophenol,  CgH4(OH).N'H2,  which  are  said  to  be  harmless. 
Paraphenacetin,  in  doses  ranging  from  8  to  20  grains  for  adults, 
and  from  2  to  3  grains  for  children,  is  said  to  be  a  valuable  anti- 
pyretic and  anti-neuralgic,  without  producing  nausea,  vomiting, 
cyanosis,  or  disagreeable  after-effects.  Being  nearly  insoluble,  it  is 
best  given  in  the  form  of  powders.  The  dose  of  orthophenacetin 
required  to  produce  the  same  effect  is  larger  than  that  of  the 
para- compound,  which  is  that  of  the  British  and  German  Pharma- 
copoeias. 

According  to  Renter  {Fharm.  Zeit.,  1891,  page  185)  phena- 
cetin is  liable  to  contain  unconverted  para-jphenethidine,  which 
appears  to  be  poisonous  in  very  small  doses,  if  taken  for  some  time, 
producing  nephritis  and  albuminuria.  To  detect  the  impurity. 
Renter  melts  2  J  grammes  of  chloral  hydrate  at  100°,  and  adds 
0"5  gramme  of  the  sample.  On  agitation  the  phenacetin  dissolves, 
and,  if  pure,  the  solution  will  remain  colourless  when  heated  on 
the  water-bath  for  five  minutes,  though  after  longer  heating  it  will 
assume  a  rose  tint.  In  presence  of  para-phenethidine,  an  intense 
coloration,  ranging  from  red- violet  to  blue- violet,  is  produced  in 
two  or  three  minutes  at  most. 

S.  Liittke  detects  diamidophenols  or  diamidoph&natols  in 
phenacetin  by  grinding  0*5  gramme  of  bleaching  powder  to  a  fine 
paste  with  hydrochloric  acid,  and  adding  about  0"03  of  the  sample, 
when  a  red  colour  will  be  produced. 

The  lower  price  of  acetanilide,  and  its  close  physical  resemblance 
to  phenacetin,  have  suggested  the  possibility  of  the  partial  or  com- 
plete substitution  of  the  former  body  for  the  latter,  and  a  flagrant 
instance  of  such  a  practice  is  actually  on  record  {Fharm.  Jour.,  [3], 
xxi.  377).  The  presence  of  5  per  cent,  of  acetanilide  lowers  the 
melting-point  of  the  sample  to  127°— 128°. 

H.  Schwartz  {Pharm.  Jour.,  [3],  xviii.  1085)  recommends 
that  1  gramme  of  the  suspected  sample  should  be  heated  with  2 
c.c.  of  caustic  soda  solution,  a  fragment  of  chloral  hydrate  or  a  few 
drops  of  chloroform  added,  and  the  mixture  again  gently  heated. 
With  phenacetin  the  odour  is  aromatic  and  not  disagreeable,  but 
in  presence  of  acetanilide,  the  penetrating  and  repulsive  smell  of 


84  PHENACETIN. 

phenyl-carbamine,  CgHg.NC,  is  produced.  On  boiling  the 
sample  with  caustic  soda  solution,  oily  drops  of  aniline  separate  if 
acetanilide  be  present  in  considerable  quantity.  If  the  cooled  liquid, 
together  with  the  separated  globules,  be  shaken  with  ether,  and  the 
ether  separated  and  evaporated,  the  residue  when  dissolved  in  water 
and  treated  with  a  drop  of  carbolic  acid,  and  a  clear  solution  of 
bleaching  powder  added,  gives  a  blue-green  coloration  changed  to 
onion-red  by  hydrochloric  acid,  and  restored  by  ammonia.  (See  also 
Jour.  Soc.  Chem.  Ind.,  vii.  772.) 

For  the  detection  of  acetanilide  in  phenacetin,  M.  J.  Schroder 
recommends  that  0'5  gramme  of  the  sample  should  be  boiled  with 
8  c.c.  of  water,  and  the  liquid  filtered  when  cold  from  the  recrystal- 
lised  phenacetin.  The  filtrate  is  boiled  with  a  little  potassium 
nitrite  and  dilute  nitric  acid,  a  solution  of  mercurous  nitrate  con- 
taining a  little  nitrous  acid  added,  and  the  whole  again  boiled.  A 
red  colour  will  be  obtained  if  the  proportion  of  acetanilide  in  the 
sample  exceeds  2  per  cent. 

If  1  gramme  of  a  mixture  of  equal  parts  of  phenacetin  with 
acetanilide  be  shaken  with  200  c.c.  of  water,  the  whole  of  the 
acetanilide  goes  into  solution  together  with  0'130  gramme  of 
phenacetin,  while  the  remainder  of  the  phenacetin  remains  in- 
soluble. If  this  be  separated,  its  weight,  when  corrected  by  an 
addition  of  0*130,  will  represent  the  phenacetin  present  in  1 
gramme  of  the  sample  (Pharm.  Jour.,  [3],  xxi.  377). 

Phenacetin  has  been  made  official  in  the  German  Pharmacopoeia 
(1890),  the  maximum  dose  being  1  gramme.  It  is  stated  to 
melt  at  135°,  and  dissolve  in  1400  parts  of  cold,  70  of  boiling, 
water,  and  16  of  spirit  to  form  neutral  solutions.  It  is  dis- 
tinguished from  exalgin  and  antifebrin  by  boiling  O'l  gramme 
for  a  minute  with  1  c.c.  of  hydrochloric  acid,  adding  10  c.c.  of 
water,  filtering,  and  adding  to  the  filtrate  3  drops  of  a  3  per 
cent,  solution  of  chromic  acid,  when  a  ruby-red  colour  will  be 
gradually  developed.  (See  Pharm.  Jour.,  [3],  xxi.  978.)  Strong 
sulphuric  acid  should  dissolve  phenacetin  without  becoming  coloured, 
while  a  saturated  solution,  if  free  from  phenol  and  acetanilide,  will 
not  become  turbid  on  adding  bromine-water.  The  description  of 
phenacetin  in  the  British  Pharmacopoeia  additions  (1890)  closely 
corresponds  with  the  above.      The  dose  is  from  5  to  10  grains. 

Meth7jl-phenacetin,  C6H4(O.C2H_^).N(CH3)(C2H30).  This  body 
is  prepared  by  treating  para-phenacetin  in  xylene  solution  with 
sodium,  and  causing  the  resultant  sodium -derivative  to 
react  with  methyl  iodide  (Pharm.  Jour.,  [3],  xxi.  81).  The 
new  product  distils  at  about  300°  C.  as  an  oil,  which  crystallises 
on  standing.     It  may  be  purified  by  recrystallisation  from  alcohol 


METHACETIN.  85 

or  ether,  when  it  forms  colourless  crystals,  moderately  soluble  in 
water,  and  having  marked  narcotic  as  well  as  antipyretic  characters. 

Amido-paraphenacetin,  C6H4(O.C2H5).NH(CO.CH2.NH2).  The 
hydrochloride  of  this  base  is  readily  soluble  in  water  and  alcohol, 
and  has  been  introduced,  under  the  name  of  " phenocollum  hydro- 
chloricum,'*  as  an  antipyretic  and  antirheumatic.  Prolonged  boiling 
with  alkalies  splits  it  into  para-phenethidine  and  glycocine. 

Formyl-paraphenethidine^  CgH4(O.C2H5).NH(CO.H), though  hav- 
ing a  constitution  similar  to  acet-phenethidine,  appears  to  have 
no  antipyretic  properties,  but  has  been  suggested  as  an  antidote 
in  cases  of  poison iiug  by  strychnine. 

Methacetin  is  the  commercial  name  of  para-acet-anisidine, 
CgH4(O.CH3).]SrH.C2H30.  It  is,  consequently,  the  lower  homologue 
of  phenacetin  (page  81).  It  forms  a  crystalline  powder  or 
small  lustrous  scales  or  plates,  odourless,  but  of  a  faintly  bitter 
taste.  It  melts  at  127°  C,  and  at  a  higher  temperature  boils 
and  distils  unchanged.  It  dissolves  in  526  parts  of  cold,  or  12 
of  boiling,  water,  and  is  easily  soluble  in  alcohol,  acetone,  chloro- 
form, and  dilute  acid  and  alkaline  liquids.  It  is  less  soluble  in 
benzene,  and  only  with  difficulty  in  ether,  carbon  disulphide, 
petroleum  spirit,  and  oil  of  turpentine,  but  dissolves  freely,  on 
warming,  in  glycerin  and  fixed  oils.  In  its  general  reactions 
and  physiological  effects,  metacetin  closely  resembles  phenacetin, 
though  according  to  some  authorities  it  has  a  less  powerful,  and 
according  to  others  a  more  powerful,  action.  Its  efficacy  in  cases 
of  neuralgia  and  rheumatism  is  said  to  greatly  exceed  phenacetin, 
from  which  it  may  be  distinguished  by  its  physical  characters, 
or  by  heating  it  with  a  quantity  of  water  insufficient  for  its 
solution.  When  thus  treated,  methacetin  melts  and  solidifies 
again  on  cooling,  whereas  phenacetin  undergoes  no  apparent 
change.  1  c.c.  of  hydrochloric  acid  dissolves  O'l  gramme  of 
methacetin  very  easily,  whereas  the  same  quantity  of  phenacetin  is 
mainly  undissolved. 

DiAMIDOPHENOLS.       CgH3(OH)(NH2)2. 

These  bodies  are  weak  bases,  forming  salts  which  crystallise 
well  and  give  aqueous  solutions  which  turn  brown  in  the  air; 
and  are  coloured  an  intense  violet  or  dark  red  by  potassium 
bichromate,  ferric  chloride,  or  bleaching  powder. 

Triamidophenol.     CgH2(OH)(NH2)3. 

This  body  is  an  unstable  base  resulting  from  the  complete 
reduction  of  picric  acid,  CgIl2(OH)(N02)3,  in  acid  solutions. 
If  alkaline  reducing  agents  be  employed,  the  action  does  not 
proceed  beyond  the  formation  of  dinitro-amido-phenol  or 
picramic  acid,  C6H2(0H)(NH2)(:N^02)2  (see  Part  I.  page  143). 


86 


PHENYLENE-DIAMINES. 


A  dilute    solution    of    triamidophenol    is    coloured  deep  blue   by 
ferric  chloride. 

Phenylene-diamines.    Diamidobenzenes. 

Three  modifications  of  phenylene-diamine  or  diamido-benzene, 
CgH^(NH2)2,  are  known,  differing  from  each  other  in  properties 
according  to  the  positions  of  the  amido-groups,  thus : — 


Ortho-Compound. 
1:2 

Meta-Compound. 
1:3 

Para-Compound. 
1:4 

Appearance, 

. 

Tablets  or  plates. 

Crystalline  mass. 

Tablets   or   small 
plates. 
140» 

Melting-point, 

.      . 

102°-103° 

63' 

Boiling-point, 

.       . 

252° 

287° 

267' 

Characters     of 
chloride, 

hydro- 

Groups  of  radiating 
needles;  readily 
soluble. 

Concentrically  ar- 
ranged crystals. 

Readily      soluble 
tablets ;       very 
sparingly  soluble 
in  hydrochloric 
acid. 

Reaction  in  neutral  solu- 
tion       with     sodium 
nitrite. 

Separation  of 
amido-azo- 
phenyleneas 
a  colourless  oily 
liquid. 

Yellow  or  brown 
coloration,      or 
precipitate      of 
triamidoazo- 
benzene. 

No  reaction. 

Ortho-phenylene-diamine  is  distinguished  from  its  isomerides 
by  its  reaction  with  sodium  nitrite,  and  by  the  separation  of 
ruby-red  needles  on  adding  ferric  chloride  to  the  solution  of  its 
hydrochloride.  On  treating  an  alcoholic  solution  of  the  base 
with  a  drop  of  phenanthraquinone  dissolved  in  glacial  acetic  acid, 
and  boiling  for  a  short  time,  a  bright  yellow  precipitate  of 
diphenylene-quinoxaline,  C20HJ2N2'  ^^  formed.  It  con- 
sists of  small  needles  which  are  coloured  a  deep  red  by  strong 
hydrochloric  acid,  and  its  production  affords  the  most  delicate 
reaction  for  ortho-phenylenediamine.  Its  isomerides  do  not  give 
the  reaction,  but  its  homologue,  ortho-toluylenediamine, 
behaves  similarly. 

Meta-phenylene-diamine  may  be  prepared  by  the  reduction  of 
meta-dinitrobenzene  (Part  I.  page  178,  footnote).  It  often  remains 
in  a  state  of  superfusion  for  some  time,  but  is  instantly  solidified  by 
adding  a  crystal  of  the  solid  substance.  Metaphenylene-diamine  is 
sparingly  soluble  in  water,  the  solution  being  alkaline  in  reaction.  It 
is  readily  soluble  in  ether,  and  may  be  extracted  by  this  solvent  from 
alkaline  aqueous  liquids.  It  is  a  di-acid  base,  the  hydrochloride 
being  CgH4(NH2)2,2IICl.  The  reaction  of  metaphenylenediamine 
with  sodium  nitrite  is  characteristic  and  extremely  delicate.  It  is 
due  to  the  formation  of  Bismarck  or  phenylene  hroiun  (Part  I.  page 


DIAMIDO-BENZENES.  87 

180),  and  b}'-  means  of  it  one  part  per  million  of  nitrous  acid  can 
be  detected  in  water. 

Metaphenylenediamine  possesses  marked  poisonous  properties, 
its  physiological  action  resembling  that  of  the  leucomaines  and 
ptomaines.  Dubois  and  Vignon  {Compt.  Rend.,  evil.  533) 
experimented  on  dogs,  and  found  that  a  dose  of  O'l  gramme  per 
kilogramme  of  the  animal  produced  salivation,  vomiting,  diarrhoea, 
abundant  excretion  of  urine  at  intervals,  and  death  by  coma  in 
twelve  to  fifteen  hours.  Besides  these  severer  symptoms,  all  those 
of  intense  influenza  were  produced,  such  as  acute  coryza  and  sneezing, 
coughing,  and  extreme  depression. 

Para-phenylene-diamine  occurs  in  aniline  tailings  (page  67).  It 
may  be  prepared  by  the  reduction  of  paranitracetanilide.  It  is  but 
slightly  soluble  in  water,  but  readily  in  alcohol  and  ether.  When 
heated  with  dilute  sulphuric  acid  and  manganese  dioxide  it  yields 
q  u  i  n  0  n  e,  CgH^Og,  which  reaction  distinguishes  it  from  its  iso- 
mer! des.  On  passing  sulphuretted  hydrogen  through  a  solution  of 
the  hydrochloride,  and  then  adding  ferric  chloride,  thionine  or  Lauth!s 
violet  is  formed  (Part  I.  page  285). 

Para-phenylenediamine  possesses  poisonous  properties  similar  to 
those  of  meta-phenylenediamine,  but  death  occurs  more  rapidly  than 
with  the  latter  base.  It  also  exerts  a  special  action  on  the  eye, 
which  is  gradually  forced  out  of  its  orbit  by  the  swelling  of  the  con- 
junctiva or  intra-orbital  cellular  tissue;  while  the  lachrymal  glands 
are  blackened  by  a  deposit  of  pigment  (compare  "Toluylene- 
diamines"). 

Dimethyl-par aphenylenediamine,  H2N.  €5114.^(0113)2,  may  be  ob- 
tained by  the  reduction  of  nitrosodimethyl-aniline  or  of  helianthin 
(Part  I.  pages  188,  211).  A  neutral  solution  of  the  hydrochloride 
is  coloured  a  beautiful  purple  by  ferric  chloride ;  and  on  treating  it 
with  a  hydrochloric  acid  solution  of  sulphuretted  hydrogen,  and 
then  adding  ferric  chloride  till  the  smell  of  sulphuretted  hydrogen 
has  disappeared,  a  fine  blue  coloration  is  obtained,  due  to  the  for- 
mation of  methylene  blue  (Part  I.  page  285).  This  reaction  is  the 
most  delicate  test  for 

TOLUYLENE-DIAMINES.     DiAMIDOTOLUENES.     CgH3(OH3)(!N'H2)2. 

These  bases  closely  resemble  the  phenylene-diamines.  The  ortho- 
jpara-modification  (OH3  :  NHg  :  NHg  =  1:2:4)  is  obtained  by  the 
reduction  of  ordinary  dinitro toluene.  It  melts  at  88°,  is  used  for 
the  production  of  toluylene  red  and  toluylene  orange.  The  1:3:4 
(meta-para)  modification  is  obtained  by  nitrofying  acet-paratoluide, 
saponifying,  and  reducing.^     Janovsky   {Jour.  Soc.  Chem.  Ind.y 

^  This  modification  appears  to  be  identical  with  the  paratoluylenediamine 
isolated  by  Hell  and  Schoop  from  aniline  tailings  [Berichte,  xii.  723). 


88 


TOLUYLENE-DIAMINES. 


ix.  383)  gives  the  following  table  of  reactions  of  neutral  or  slightly 
acid  solutions  of  the  two  isomeric  toluylene-diammes  : — 


Eeagent. 


Ferric  chloride. 

Potassium  bichromate. 
Potassium  ferricyanide. 
Bromine  water. 
Platinic  chloride. 
Auric  chloride. 

Potassium  nitrite. 


Solution    of     bleaching 
powder. 


a-Toluylene-diamine. 
CH3:NH2:NH2  =  1:2:4 


No  change  at  first ;  after 
standing  for  a  long  time 
an  orange  coloration. 


YeUowish-brown 
tion. 


colora- 


Olive-green 
plates. 

Yellowish-white 
tate. 

Yellowish-brown 
tion. 


crystalline 
precipi- 
colora- 
Brown  precipitate. 


In  very  dilute  solutions  a 
golden-brown  coloration ; 
in  concentrated  a  brown 
precipitate. 

B,eddish  -  brown  colora- 
tion and  then  a  light 
brownish-yellow  precipi- 
tate. 


/3-ToluylenB-diamine. 
CH3:NH2:NH2  =  1:3:4 


Wine-red  coloration. 


Reddish-brown       precipi- 
tate. 

Dark-red  coloration. 


Brown  flocks  and  magenta- 
red  solution. 


Reddish-brown 
tate. 


precipi- 


Red  solution  with  blue 
reflex  and  metallic  mir- 
ror in  the  cold. 

No  coloration,  but  a  sal- 
mon-coloured precipi- 
tate. 


Dark-red  coloration,  then 
an  olive-green  precipi- 
tate. 


The  foregoing  reactions  are  available,  even  in  presence  of  other 
substances,  for  the  detection  and  identification  of  the  toluylene- 
diamines,  which  often  result  from  the  reduction  of  azo-dyes. 

The  toluylene-diamines  are  powerful  poisons  (compare  "  Meta- 
phenylenediamine,"  page  87).^ 

Benzidine.     Dipara-amido-diphenyl. 

Ci2Hi2N2  =  NHj.C8H,.C,H,.NH2  (1,  4  :  1,  4). 

This  body  is  obtained  by  the  reduction  of  diparanitro-diphenyl, 
NOg.CgHg.CgH^JSTOg,  by  nascent  hydrogen  (tin  and  hydrochloric 
acid).  A  readier  method  of  preparation  is  the  following : — An 
alcoholic   solution   of    10   parts    of   azobenzene,    CgH^.N :  N.CgHg, 

^  Engel  and  Kiener  {Compt.  Rend.,  cv.  465;  Jour.  Chem.  Soc,  liv.  81) 
find  the  symptoms  to  vary  considerably  according  to  the  time  required  to  pro- 
duce death,  which  ranges  from  a  few  hours  in  acute  cases  to  several  weeks  in 
chronic  cases.  When  death  ensues  in  a  few  days,  there  is  always  icteria,  and 
often  hsemoglobinuria,  and  the  urine  is  loaded  with  fat  and  yellow  and  brown 
pigment-granules,  which  sometimes  contain  iron.  This  ferruginous  pigment 
accumulates  in  the  spleen  and  marrow,  and  seems  to  be  formed  from  the  haemo- 
globin in  the  protoplasm  from  the  cellules,  and  not  from  the  red  corpuscles. 


BENZIDINE.  89 

is  treated  with  a  solution  of  3  J  parts  of  tin  in  concentrated 
hydrochloric  acid,  and  the  liquid  warmed  for  some  time. 
Hydrazobenzene,  C6H5.NH.NH.CgH5,  is  formed,  which  by 
intramolecular  change  is  converted  into  benzidine  (dihydro- 
chloride).  Some  of  the  isomeric  ortho-para-diamido- 
diphenyl  is  simultaneously  formed,  and  a  portion  of  the 
azobenzene  is  reduced  to  aniline,  CgHg.NHg.  The  alcohol  is 
distilled  off,  the  residue  dissolved  in  water,  and  sulphuric  acid 
added.  The  nearly  insoluble  benzidine  sulphate  is  precipitated, 
while  the  sulphates  of  the  isomeric  base  and  of  aniline  remain 
in  solution.  The  precipitate  is  washed  with  dilute  hydrochloric 
^cid  (to  remove  tin  salts)  and  treated  with  ammonia,  the 
liberated  benzidine  being  crystallised  from  dilute  alcohol.  Ben- 
zidine is  also  produced  by  treating  azobenzene  with  sulphur 
dioxide.  Benzidine  is  manufactured  on  a  large  scale  by  heating 
nitrobenzene  with  caustic  soda,  a  little  alcohol,  and  the  proportion 
of  zinc-dust  theoretically  sufficient  to  reduce  it  to  hydrazobenzene. 
The  product  is  washed  with  cold  dilute  hydrochloric  acid  to 
remove  oxide  of  zinc.  On  subsequently  heating  it  with  dilute 
hydrochloric  acid,  it  is  converted  into  benzidine  dihydrochloride. 

Benzidine  forms  large  pearly  plates,  which  are  colourless  when 
pure,  but  rapidly  turn  red  on  exposure  to  the  air.  It  melts  at  122°, 
and  boils  with  partial  decomposition  above  360°.  Benzidine  is 
very  sparingly  soluble  in  cold,  but  readily  in  boiling,  water,  and 
is  easily  soluble  in  alcohol  and  ether. 

Benzidine  is  a  well-defined  di-acid  base,  forming  crystallisable  salts. 
The  sulphate  is  very  sparingly  soluble  in  water,  even  when  boiling. 

On  adding  potassium  bichromate  to  a  concentrated  solution  of 
benzidine  hydrochloride,  a  deep  blue  crystalline  precipitate,  con- 
taining Ci2^8(^^2)2^^^4'  ^^  immediately  formed.  The  same 
precipitate  is  formed  on  warming,  even  in  very  dilute  solutions. 

When  chlorine-water  is  added  in  small  quantity  of  a  solution 
of  benzidine  hydrochloride,  the  liquid  assumes  a  fine  blue  colour, 
which  on  further  addition  of  chlorine-water  changes  to  green ;  and 
ultimately,  when  the  chlorine  is  in  excess,  a  flocculent  red  pre- 
cipitate is  formed,  apparently  containing  C^gH^OlgNgO,  soluble 
in  alcohol  and  ether,  and  forming  a  colourless  compound  on 
reduction.  Bromine-water  and  a  solution  of  bleaching  powder  act 
similarly;  but  in  presence  of  a  large  quantity  of  free  hydrochloric 
acid  bromine  forms  tetrabrombenzidine,  melting  at  285°. 
With  nitrous  acid,  solutions  of  benzidine  salts  react  to  form 
tetrazo-compounds  which  react  with  phenols,  phenol- 
sulphonic  and  carboxylic  acids,  amidosulphonic  acids,  &c.,  to 
form  the  important  class  of  bodies  known  as    "  tetrazo-dyes,"  of 


90 


NAPHTHYLAMINES. 


which  congo-red  is  the  type  (Part  I.  page  206),  and  which  are 
remarkable  for  dyeing  cotton  without  a  mordant, 

Orthotolidine.  NH2.C6H3(CH3).(CH3)C6H3.NH2.  This  base 
is  homologous  with  benzidine,  and  is  prepared  from  ortho-nitro- 
toluene  by  the  same  process  by  which  benzidine  is  prepared  from 
nitrobenzene.  It  melts  at  128°,  and  presents  a  close  resemblance  to 
benzidine.  The  tetrazo-dyes  prepared  from  it  are  less  readily 
altered  by  acids  than  are  the  similar  dyes  prepared  from  benzidine. 


NAPHTHYLAMINES  AND  THEIR  ALLIES. 

When  naphthalene,  C^oHg,  is  treated  cautiously  with  nitric 
acid,  nitronaphthalene,  Cj^qH7(N02),  is  formed,  and  this  by 
treatment  with  reducing  agents  is  converted  into  amido-naph- 
thalene  or  naphthylamine,  CioHy(NH2).  These  reac- 
tions are  strictly  analogous  to  those  by  which  aniline  is  prepared 
from  benzene,  and  the  product  is  known  as  alpha-n  a  p  h  t  h  y  1- 
amine.  But  by  other  reactions  the  isomeric  beta-n  a  p  h  t  h  y  1- 
amine  may  be  obtained.  These  two  bodies  differ  from  each 
other  in  a  notable  manner,  as  indicated  in  the  following  table : — 


Alpha- 

Beta- 

Naphthylamine. 

Naphthylamine. 

OH        C.NHo 

CH       CH 

/\/\ 

/\/\    _ 

HC 

C 

CH 

HC 

C 

C.NH2 

Structural  Formula,    . 

II 

1 

1 

c 

HC 

C 

CH 

HC 

CH 

\y^ 

X/\^ 

CH        CH 

CH     cn 

Melting-point,  .     .     . 

50° 

112° 

Boiling-point,    .     .     . 

300° 

294° 

Odour, 

Disagreeable;  persistent. 

None. 

Appearance,  .... 

Flat  needles  or  prisms. 

Pearly  plates. 

Reactions  of  hydrochlo- 

.ride  in  solution  :— 

With  ferric  chloride,   . 

Blue  precipitate. 

No  reaction. 

With    nitrous  acid  in 

Yellow  colour,   turned 

No  reaction. 

alcoholic    or    acetic 

crimson    by    hydro- 

acid solution. 

chloric  acid. 

With  sulphanilic  acid 

Red  coloration. 

... 

and  sodium  nitrite. 

followed   by  hydro- 

chloric acid, 

ALPHA-NAPHTHYLAMINE.  91 

a-Naphthylamine.    CioH^.NHg. 

This  base  is  obtained  (as  already  stated)  by  the  reduction  of 
nitronaphthalene,  or  by  heating  a-naphthol  with  the  double  com- 
pound of  chloride  of  calcium  and  ammonia.^ 

a-Naphthylamine  has  a  most  disgusting  and  persistent  odour,  re- 
sembling that  of  faeces.  It  turns  violet  or  brown  in  the  air,  but  when 
purified  by  sublimation  this  change  occurs  very  slowly,  and  only  on 
exposure  to  air  and  light.     It  is  slightly  volatile  with  steam. 

a-Naphthylamine  is  nearly  insoluble  in  water,  but  very  soluble 
in  alcohol  and  ether.  It  forms  a  series  of  readily-crystallisable, 
easily-soluble  salts.  On  adding  ammonia  to  a  solution  of  the  sul- 
phate, the  free  base  is  precipitated  in  white  silky  needles. 

On  adding  ferric  chloride  to  a  solution  of  a-naphthylamine,  or 
of  one  of  its  salts,  an  azure  blue  precipitate  ofnaphthamein  is 
produced,  which  rapidly  becomes  purple,  but  is  unchanged  by  treat- 
ment with  sulphurous  acid.  Other  oxidising  agents  (e.^.,  chromic 
acid,  bleaching  powder)  produce  precipitates  varying  in  colour  from 
blue  to  violet  or  red. 

On  adding  an  alcoholic  solution  of  nitrous  acid  to  a  solution  of 
a-naphthylamine  in  alcohol  or  glacial  acetic  acid,  a  yellow  colour  is 
produced,  which,  on  adding  a  little  hydrochloric  acid,  changes  to 
an  intense  violet  or  magenta  colour ;  or,  in  presence  of  only  traces 
of  naphthylamine,  to  a  reddish  colour. 

If  to  a  cold  solution  of  alpha-naphthylamine  sulphanilic  acid  and 
sodium  nitrite  be  added,  a  red  colour  is  produced  on  adding  hydro- 
chloric acid,  owing  to  the  formation  of  amidonaphthyl- 
azobenzene-sulphonic  acid,  CioHg(NH2).!N'2-^6^4(^^3-^)- 

a-Naphthylamine  is  used  for  the  preparation  of  Magdala  red  (Part 
I.  p.  257),  certain  azo-dyes,  and  naphthalene  fancy-colours  on  cotton. 

Commercial  u-naphthylamine  ought  to  melt  at  50°  C,  and  be 
almost  completely  soluble  in  dilute  hydrochloric  acid.  Naphthalene, 
the  presence  of  which  causes  incomplete  solubility,  may  be  deter- 
mined by  distilling  the  acidulated  solution  in  a  current  of  steam, 
agitating  the  distillate  with  ether,  separating  the  ethereal  layer, 
evaporating  it  at  a  low  temperature,  and  weighing  the  residue. 

^  On  a  large  scale,  a-naplitliylamine  is  prepared  in  a  manner  very  similar  to 
that  employed  for  the  production  of  aniline.  Nitronaphthalene  is  reduced  by 
iron  and  hydrochloric  acid  at  a  temperature  of  about  50°.  When  the  reduction 
is  complete,  milk  of  lime  is  added,  and  the  naphthylamine  distilled  off  by  the 
aid  of  superheated  steam.  The  crude  product  is  purified  by  redistillation,  when 
it  is  obtained  as  a  nearly  colourless  oil,  which  solidifies  to  crystalline  cakes  of  a 
greyish  colour.  It  appears  to  be  wholly  free  from  )8-naphthylaraine,  but 
contains  an  impurity  which  is  probably  l:l'-naphthylene-diamine, 
CioHe(NH2)2  (0.  N.  Witt,  Dingl.  Polyt.  Jour.,  cclxv.  225). 


92  THERMINE. 

P  Naphthylamine.    CioH^.NHg. 

This  modification  of  amidonaphthalene  is  most  readily  obtained  by 
heating  ^-naphthol  under  pressure  with  ammonia  at  160°,  or  with 
the  double  compound  of  zinc  chloride  and  ammonia  at  200°— 210°. 

^-Naphthylamine  is  odourless  and  more  stable  than  the  a-modi- 
fication.  It  volatilises  in  a  current  of  steam,  and  is  slightly  soluble 
in  cold,  more  readily  in  hot,  water,  the  solution  exhibiting  a  blue 
fluorescence,  which,  however,  is  not  shown  by  /3-naphthylamine 
salts.  |8-Naphthylamine  gives  no  coloration  with  oxidising  agents, 
nor  with  nitrous  and  hydrochloric  acids  in  alcoholic  solution. 

Commercial  (3 -naphthylamine  ought  to  melt  at  112°  C,  and  be 
completely  soluble  in  dilute  hydrochloric  acid. 

TETRAHYDR0-/5-NAPHTHYLAMINE.       CjoH^^.NHg. 

This  base  has  been  introduced  into  medicine  under  the  name  of 
"  T  h  e  r  m  i  n  e."  It  is  a  colourless,  slightly  viscous  liquid,  of 
peculiar  odour.  It  is  a  strong  base,  a  drop  soon  becoming  converted 
into  a  crystalline  mass  of  the  carbonate  on  exposure  to  air.  The 
hydrochloride  forms  well-defined  white  crystals,  melting  at  237°, 
and  readily  soluble  in  water,  alcohol,  and  amylic  alcohol. 

The  physiological  efi'ects  of  thermine  embrace  the  two  strongly - 
marked  characteristics  of  mydriasis  (accompanied  by  pain)  and 
elevation  of  the  temperature,  which  latter  effect  has  been  observed 
to  the  extent  of  4J°  C 

Naphthylamine-Sulphonic  Acids. 

When  treated  with  dilute  sulphuric  acid,  the  naphthylamines 
dissolve  easily  with  formation  of  sulphates,  but  by  the  action  of 
concentrated  sulphuric  acid  at  a  high  temperature  they  are  con- 
verted into  sulphonic  acids.  Thus  when  a-naphthylamine  is  heated 
with  fuming  sulphuric  acid,  two  isomeric  sulphonic  acids  are  formed, 
one  of  which  is  readily  soluble  in  water,  while  the  other  is  only 
sparingly  soluble.  The  latter  modification  crystallises  in  small 
lustrous  needles,  and  in  aqueous  solution  exhibits  a  beautiful 
fluorescence.  Similarly,  /3-naphthylamine  yields  on  sulphonation 
several  isomeric  acids.  According  to  A.  G.  Green  (Ber.,  xxii. 
721),  at  moderate  temperatures  (100°  C.),  and  with  ordinary  sul- 
phuric acid,  the  product  is  a  mixture  of  a  and  y  acids,  having 
their  sulphonic  groups  in  the  a-position ;  while  at  a  higher  tem- 
perature (160°— 170°)  /5  and  S  modifications  are  produced,  having 
their  sulphonic  groups  in  the  /9-position.  The  ammonium  salt  of 
the  /5-acid  is  less  soluble  than  the  three  isomeric  salts,  and  by  this 
means  the  ^-acid  can  readily  be  isolated. 

The  a-naphthylamine-sulphonic  acids  may  also  be  obtained 
by  treating  nitronaphthalene,  C^jHyNOg,  with  fuming  sul- 


NAPHTHALENE-DIAMINES. 


93 


phuric  acid,  and  reducing  the  resultant  nitronaphthalene-sulphonic 
acid,  CioHg(]Sr02)(S03H),  with  iron  and  hydrochloric  acid.  Two 
isomeric  amido-sulphonic  acids  are  obtained  in  this  case  also. 

The  naph thy laraine-sul phonic  acids  are  also  conveniently  pre- 
pared by  heating  the  corresponding  naphthol-sulphonic  acids  (Part 
I.  pages  194,  207,  208)  with  ammonia  under  pressure. 

Naphthylamine-disulphonic  acids  may  be  obtained 
by  reactions  similar  to  those  described  above.  Two  of  these 
derivatives  of  y8-naphthylamine  are  technically  known  as  "  Amido- 
acid  R"  and  "Amido-acid  G."  The  latter,  or  y-acid,  is  not  capable 
of  reacting  with  diazo-compounds,  but  the  first,  or  a-acid,  produces 
colouring  matters  which  yield  colourless  solutions  on  reduction.^ 


N  aphthylene-Diamines.    CioH6(NH2)2. 

These  bases  may  be  formed  by  heating  the  corresponding 
dihydroxynaphthalenes  with  ammonia,  by  the  reduction  of  the 
dinitronaphthalenes,  and  in  other  ways. 

The  following  table  exhibits  their  leading  properties  : — 


Position  of 

the  Amido-Groups. 

ai,  a2 

ai,  0-3     . 

ai,  a4 

«!,  ^1 

Mode  of  preparation, 

From  a-nitro- 

From  a-di- 

From  i8-di- 

By  reducing 

From  aj  -  a3. 

naphthyl- 

nitro-naph- 

nitro-naph- 

azo-com- 

Dihydroxy- 

amine  by  re- 

thalene. 

thalene. 

poundsof/3- 

naphthalene. 

duction,  and 

napthyl- 

from  azo- 

amine. 

compounds 

of  a-naph- 

thylamine. 

Form  of  crystals,     . 

Leaves. 

Needles. 

Needles. 

Plates. 

Needles. 

Melting-point,     .    . 

120°  C. 

189° -5  C. 

66° -6  C. 

95°  C. 

189°  C. 

Hydrochloride,  .    . 

Plates. 

Needles  (?). 

... 

Plates. 

Plates. 

Sulphate 

... 

Needles. 

... 

Plates. 

Needles. 

Reaction  of  the  hy- 

Green colora- 

Blue colora- 

Chestnut- 

Green,    then 

Blue  colora- 

drochloride    with 

tion. 

tion;   then 

brown  pre- 

yellow 

tion;  then 

ferric  chloride, 

blue  precipi- 
tate. 

cipitate. 

coloration ; 
brown  pre- 
cipitate. 

precipitate. 

Action    of    nitrous 

Sol.  tetrazo- 

Sol.  tetrazo- 

Vermilion 

••• 

Sol.  tetrazo- 

acid, 

compound. 

compound. 

precipitate. 

compuund. 

Action  of  the  azo  dye- 

Do  not  dye. 

Dye  the  fibre. 

••• 

... 

Dye  the  fibre. 

stuffs   on  unmor- 

danted  cotton. 

^  For  further  information  respecting  the  naphthylamine-disulphonic  acids 
and  the  naphthalene  derivatives  generally,  see  various  papers  by  Armstrong 
and  Wynne  {Jour,  and  Proc.  Chem.  Soc,  1890,  1891),  and  the  article  by 
Wynne  in  Thorpe's  Dictionary  of  Applied  Chemistry,  ii.  6i9  et  seq. 


94 


AMIDO-NAPHTHOLS. 


Amidonaphthols.    CioH^COHX^H^). 

These  bodies  are  unstable  bases  obtained  by  the  action  of 
reducing  agents  on  the  nitro-  or  nitroso-naphthols,  or  on  certain 
azo-dyes.  The  following  table  shows  the  leading  differences  of 
the  principal  members  of  the  group  : — 


a-  Amido- 

/3-Amido- 

a-Amido- 

a-naphthol. 

a-naphthol. 

/3-naphthol. 

Relative  position  of 

1:4 

1:2 

2:l(or4) 

the  OH  and  NHg 

groups. 

Mode  of  formation. 

Reduction    of     1:4 

Reduction    of    1:2 

Reduction    of   the 

nitro  -  a-naphthol 

nitro  -  a-naphthol 

nitro-/3-naphthol, 

melting  at  164°;  or 

melting  at  128°;  or 

melting  at  103°;  of 

of  Orange  I.  (Part 

of  nitroso-a-naph- 

nitroso-^-naph- 

I.  page  284). 

thol. 

thol;  or  of  Orange 
II.  (Part  I.  page 
184). 

Characters  of  free 

Unstable. 

Unstable. 

Colourless    scales ; 

base. 

slightly  soluble  in 
water ;  oxidised 
in  the  air.  Ethe- 
real solution  ex- 
hibits violet  fluo- 
rescence. 

Reaction  on  agitat- 

Dirty green  colora- 

Permanent       grass- 

Brown  coloration. 

ing  alkaline  solu- 

tion, changing  to 

green  colour,  and 

tion  with  air. 

yellow. 

green    scum    sol- 
uble    in    alcohol 
to      pure      green 
solution.  Or  violet 
naphthoquin- 
onimide— 

Reaction  with  bro- 

Yellowish-white 

Yellowish  or  green 

mine  water. 

needles   precipi- 

precipitate     (the 

tated,  even  in  very 

same   with   ferric 

dilute  solutions. 

chloride). 

Characters  of  hydro- 

Long white  needles 

White  laminsB. 

chloride. 

or  acicular  plates. 

White         lustrous 

With      bleaching 

needles;   readily 

powder         yields 

soluble  in  water, 

C20H12N3CI,  which 

but     only     spar-  | 

separates       from 

tngly    in    dilute  ; 

acetic   acid    solu- 

hydrochloric acid. 

tion    in    needles. 

melting  at  85°  and 

exploding  at  130°. 

Product   of   oxida- 

Theoretical yield  of 

/5-naphthoquinone. 

/3-naphthoquinone. 

tion   with    chro- 

a-naphthaquinone. 

mic  acid  mixture. 

Amidonaphthol-sulphonic  Acids.  These  bodies  result  from 
the  reduction  of  azo-derivatives  of  the  respective  diazobenzene  com- 
pounds of  naphthol-sulphonic  acids.  Thus,  for  instance,  by  treat- 
ing the  four  known  modifications  of  /3-naphthol-monosulphonic  acid 
with  stannous  chloride,  0.  N.  Witt  obtained  the  following  amido- 
sulphonic  acids  {Berichte,  xxi.  3468,  3489): — 


AMIDONAPHTHOL-SULPHONIC   ACIDS. 


95 


1.  Amido-/3-naphthol-^-sulphonic    acid,    from    Schaffer's    acid 

(Parti,  page  194). 

2.  Amido-/3-naphthol-a-sulphonic  acid,  from  Bayer's  acid  (Part 

I.  page  194). 

3.  Amido-/3-naphthol-5-sulph.onic  acid,  from  Casella's  acid  (Part 

I.  page  208). 

4.  Amiio-^-naphthol-y-sulphonic  acid,  from  Dahl's  acid. 

The  first  of  these  acids  has  recently  received  a  novel  application 
as  a  photographic  developer  under  the  name  of  eikonogen  (R. 
M  e  1  d  0 1  a,  Jour.  Soc.  Chem.  Ind.,  viii.  968).  It  may  be  obtained  by 
the  reduction  of  the  azo-dye  known  as  '*  Crocein  orange,"  "  Brilliant 
orange"  or  "Ponceau  4GB"  (Part  I.  page  184),  obtained  by  the 
reaction  of  Schaffer's  ^-naphthol-sulphonic  acid  (Part  I.  page  194) 
on  diazobenzene  chloride.  It  may  be  obtained  from  its  nitroso- 
derivative  by  dissolving  the  ammonium  or  other  salt  of  Schaffer's 
acid  in  ice-cold  water,  together  with  an  equivalent  quantity  of  sodium 
nitrite,  and  then  gradually  adding  hydrochloric  acid  to  acid  reaction, 
when  the  nitroso-acid  is  at  once  formed,  and  imparts  an  orange 
colour  to  the  solution.  The  acid  can  be  purified  by  conversion 
into  a  barium  or  calcium  salt  (Jour.  Chem.  Soc,  xxxix.  44),  or  the 
solution  may  be  at  once  reduced  to  the  amido-acid  by  treatment  with 
zinc-dust  or  stannous  chloride. 

Two  other  amid o-/5-n a p h t h o  1-m onosulphonic  acids 
are  obtainable  by  heating  with  caustic  alkali,  to  200°-280°,  the  two 
j8-naphthylamine-disulphonic  acids  respectively  obtained  by  treat- 
ing with  the  two  isomeric  ^-naphthol-disul phonic  acids  R  and  Y 
(described  in  Eng.  Patent,  1878,  :N'o.  1715).  They  differ  from  the 
amidonaphthol-sulphonic  acids,  referred  to  above,  in  yielding  diazo- 
compounds.  They  can  also  be  combined  with  various  tetrazo-com- 
pounds,  giving  blackish  violet  or  blue-black  dye-stuffs.  The  following 
table  shows  some  of  their  reactions  (Eng.  Patent,  1889,  No.  15176). 
R  salt  is  the  sodium  salt  of  y8-naphthol-disulphonic  acid : — 


R. 

Y. 

Solution  of  neutral  salts  in 
water. 

Reaction  with  ferric  chlo- 
ride. 

Reaction  with  bleaching- 
powder  solution. 

Diazo-compound. 

Combination  of  the  diazo- 
compound  with  "  R  salt" 
in  an  alkaline  solution. 

Violet  fluorescence. 

Dark  blue  coloration,  turn- 
ing to  dun  colour. 

Light        yellowish-brown 
coloration,    which    dis- 
appears rapidly  on  add- 
ing excess  of  the  reagent. 

Reddish  orange. 

Claret  red. 

Blue. 

Dirty  claret-red  coloration. 

Dark  reddish-brown  colora- 
tion, which  disappears 
graduaUy  on  adding  ex- 
cess of  the  reagent. 

Canary  yellow. 

Violet-black. 

96 


PYRIDINE    AND    ITS    ALLIES. 


PYRIDINE  BASES.    C„H,„.,K 

These  bases,  raetameric  with  aniline  and  its  homologues,  are  con- 
tained in  coal-tar  naphtha ;  in  shale-oil ;  in  peat-tar ;  in  tobacco- 
smoke  ;  and,  together  with  ammonia  and  methylamine  and  its 
homologues,  in  the  product  called  "  Dippel's  oil,"  obtained  by  the 
distillation  of  bones  and  other  animal  matters.  Pyridine  itself 
has  received  several  technological  applications,  and  is  of  great 
interest  theoretically  in  relation  to  the  alkaloids. 

Pyridine  may  be  regarded  as  benzene,  in  which  one  of  the  CH 
groups  has  been  replaced  by  N.^     Thus  :  — 

<CH ^H%^  ^CH CH^ 

^CH  CHf  >N 

CH=CH^  ^CH=CH^ 

Benzene.  Pyridine. 

The  homologous  bases  are  derived  from  pyridine  by  the  sub- 
stitution of  CHg,  CgHg,  &c.,  for  one  or  more  of  the  hydrogen  atoms, 
and  consequently  admit  of  isomeric  modification  according  to  the 
position  of  the  substituted  atoms  in  the  chain. 

The  following  is  a  list  of  the  bases  of  the  pyridine  series.     The 

^  The  relationship  between  various  organic  bodies  (hypothetical  and  other- 
wise), of  which  the  names  commence  with  the  root  pyr  is  shown  by  the  follow- 
ing formulae  (compare  page  30).  The  hydrocarbon  pyrene  has  the  constitution 
of  a  phenylene-naphthalene,  and  is  not  related  closely  to  the  bodies  tabulated 
below:  — 


\- 


Piazine. 
T^/:CH.CH: 
^  \  .CHtCH. 

Piazine  Dihydride. 
^\.CH2.CH2.|^ 

Piazine  HexahydHde 
(Diethylene-diamine). 

B»{;gg:gi^:}NH 


Quinone. 

co{:gg:gg;}co 


"{ 


Pyridine. 
:CH.CH:\pp, 


CH 


Pyridine  Dihydride. 

j^/:CH.CH:\, 

^1.CH2.CH2.r 

Pyridine  Hexahydride 
(Piperidine). 


°{ 


Pyrone. 

.CH:CH.\co 
.CH:CH./^" 


Pyrrol. 
^T^/.CH:CH. 
^^  i  .CH:CH. 


HN 


Pyrroline. 

/.CH:CH2.(. 

t.CHg.CHa.) 


Pyrrolidine. 
^^\.CH2.CH2./ 


HN 


Pyridone 
r.CHrCH. 
\.CH:CH. 


CO 


Pyrazole. 

^^(!cH:CH.r 

Pyrazoline. 
^^{iCHa.CHa.} 

Pyrazine. 

„jf(.NH.CH2.> 
^^  \  .CH2.Cfl2:f 


Pyrazolone. 


.COCH2. 


Piazine  has  merely  a  hypothetical  resistance,  and  the  dihydride  is  known  only 
through  its  diphenyl-derivative.  Pyrone  and  pyrazine,  also,  are  only  known 
by  their  derivatives.  Pyrazole,  C3H4N2,  has  been  recently  obtained  by  acting 
on  hydrazine  hydrate  with  epichlorhydrin  in  presence  of  zinc  chloride : — 

2N2H4  +  C3H5CIO  =  C3H4N2  -f-  HCl  -h  H2O  +  2NH3 . 

Pyrazole  is  a  basic  substance  crystallising  in  needles,  melting  at  70°,  and  boil- 
ing at  188°.     It  is  readily  soluble  in  water,  alcohol,  and  ether. 


PYRIDINE   BASES. 


97 


boiling-points  and  specific  gravities  are  only  approximate,  as  the 
isomeric  modifications  exhibit  sensible  differences  in  their  physical 
properties. 


Formula. 

Base. 

Boiling-Point. 

•c. 

Specific 
at  0'  C. 

Gravity 
o«22°C. 

CgHsN 

Pyridine. 

115-116 

•9858 

... 

CfiHyN 

C7H9N 
CfiHioN 

Picoline 
(o-Methyl- Pyridine). 

Lutidine 

(y-Ethyl- Pyridine). 

CoUidine. 

133-135 
154 
179 

•9613 
•9443 
•921 

•933 

C9H13N 

Parvoline. 

188 

•906 

C10H15N 

Corridine. 

211 

•974 

CuHirN 

Eubidine. 

230 

... 

1-017 

CiafligN 

Viridine. 

251 

... 

1-024 

From  the  above  table  it  is  evident  that  the  boiling-points  rise 
as  the  number  of  carbon-atoms  in  the  molecule  increases.  For  the 
first  four  members  of  the  series  the  specific  gravity  diminishes, 
with  increase  in  the  molecular  weight,  but  with  the  higher  mem- 
bers the  reverse  is  recorded  as  being  the  case.  The  lower  members 
are  miscible  with  water  in  all  proportions,  but  collidine  and  its 
higher  homologues  are  insoluble,  or  nearly  so,  in  water. 

If  a  drop  or  two  of  pyridine,  or  one  of  its  homologues,  be  warmed 
in  a  test-tube  with  a  similar  quantity  of  methyl  iodide,  the  product 
mixed  with  powdered  caustic  potash  and  moistened  with  water, 
and  heat  applied,  a  highly  characteristic  and  peculiar  odour  is  pro- 
duced, owing  to  the  formation  of  a  pyridic  dihydride.  It  resembles 
that  of  a  mixture  of  mustard  oil  and  isonitrile.  The  least  trace  of 
pyridine  or  its  homologues  can  be  detected  in  this  way.  A  some- 
what similar  odour  is  obtained  when  a  quinoline  base  is  treated  in 
the  same  manner,  but  the  aniline  bases  and  piperidine  do  not  give 
the  reaction.  The  foregoing  test,  due  to  A.  W.  H  0  f  m  a  n  n,  is 
modified  by  d  e  C  0  n  i  n  c  k  as  follows  : — 1  c.c.  of  the  base  is 
gradually  mixed  with  2  c.c.  of  methyl  iodide,  the  liquid  being 
cooled  during  the  mixing.  The  crystalline  product  is  dissolved  in 
about  5  c.c.  of  alcohol,  the  liquid  heated  to  boiling,  and  very  con- 
centrated caustic  potash  solution  dropped  in.  A  blood-red  colour 
is  produced,  and  the  liquid  finally  becomes  dark  brown  if  a  pyri- 
dine base  be  present  {Jour.  Chem.  Soc,  1.  897).  Piperidine,  spar- 
teine, cicutine,  and  the  aniline  bases  give  no  similar  reaction. 

The  bases  of   the  pyridine  series  are  tertiary  monamines,  and 

VOL.  III.  PART  II.  G 


98  PYRIDINE   BASES. 

form  with  alkyl  iodides  compounds^  which  are  not  decomposed  by 
caustic  potash,  but  yield  caustic  hydroxides  by  reaction  with  silver 
oxide  (compare  page  18). 

The  pyridine  bases  and  their  salts  exert  a  soporific  action  on  the 
higher  animals.  When  inhaled,  pyridine  acts  as  a  respiratory 
sedative.  It  has  been  successfully  used  as  a  heat  stimulant  and 
as  a  topical  antiseptic  in  diphtheria.  Penzhold  found  pyridine 
to  act  as  a  general  antiseptic,  especially  as  regards  mycelia.  On 
the  lower  animals,  pyridine  and  its  homologues  act  as  violent 
poisons,  and  have  been  successfully  employed  in  0*2  per  cent 
solution  for  destroying  the  scab-acarus  in  sheep,  the  vine-louse, 
and  other  injurious  insects.  The  pyridine  bases  appear  to  be  little, 
if  at  all,  inferior  to  nicotine  for  these  purposes,  and  have  also  been 
employed  in  disinfecting  powders. 

Isolation  of  Pyridine  Bases. 

For  the  preparation  of  the  pyridine  bases,  bone-oil,  or  the  frac- 
tion of  coal-tar  or  shale-oil  boiling  between  80°  and  250°,  should 
be  agitated  with  sulphuric  acid  diluted  with  twice  its  measure  of 
water,  the  treatment  being  repeated  to  ensure  the  complete  solution 
of  the  bases.  The  acid  liquid  is  separated  and  distilled  (or  boiled 
by  a  current  of  steam)  till  the  vapours  no  longer  redden  a  slip  of 
fir-wood  moistened  with  hydrochloric  acid,  showing  that  all  the 
pyrrol  has  been  driven  off.  The  liquid  is  then  filtered  through 
linen  to  separate  tarry  matters,  an  excess  of  caustic  soda  added, 
and  the  whole  distilled  with  steam  as  long  as  bases  continue  to 
pass  over,  as  indicated  by  the  production  of  fumes  by  contact  of 
the  vapours  with  hydrochloric  acid.  The  distillate  is  allowed  to 
cool,  and  is  then  treated  gradually  with  a  large  quantity  of  solid 
caustic  potash  or  soda,  till  the  pyridine  bases  separate  as  an  oily 
layer  on  the  surface  of  the  alkaline  ley.^  The  upper  stratum  is 
separated,  and,  if  it  contains  aniline,  fuming  nitric  acid  is  cautiously 
added  and  the  mixture  gradually  heated  to  boiling,  whereby  the 
aniline  is  destroyed,  while  the  pyridine  bases  remain  intact.^ 
Water  is  then  added,   the  precipitate  filtered  off,  and  the  filtrate 

^  Their  methiodides  (PyMel)  strongly  excite  the  brain  and  paralyse  the 
extremities. 

2  The  potash  can  be  greatly  economised,  with  a  loss  of  some  of  the  higher 
homologues,  by  rendering  the  distillate  acid  with  hydrochloric  acid,  and  con- 
centrating it  to  a  small  bulk  by  evaporation  at  a  gentle  heat  before  adding 
caustic  potash. 

3  Greville  Williams  destroys  aniline  and  its  homologues  by  heating 
with  potassium  nitrite  and  hydrochloric  acid.  Hausermann  converts  the 
aniline  into  sulphate,  which  salt  is  much  less  soluble  than  the  sulphates  of 
the  olher  bases. 


PREPARATION   OF   PYRIDINE.  99 

again  treated  with  solid  caustic  potash.  The  layer  of  bases  is 
removed,  and  further  treated  with  stick  potash  or  soda  for  several 
days,  or  until  no  more  alkali  dissolves.  It  is  only  by  prolonged 
contact  with  solid  caustic  alkali  that  the  bases  can  be  freed  from 
water,  and  it  is  absolutely  necessary  to  obtain  them  in  a  perfectly 
anhydrous  state  before  attempting  to  separate  them  by  fractional 
distillation.  This  is  a  very  tedious  operation,  but  is  greatly  facili- 
tated by  operating  in  a  vacuum,  and  by  the  employment  of  a 
Hempel's  tube  or  Henninger's  or  Glynsky's  bulbs  (Vol.  I.  page 
14  ;  Vol.  II.  501).  Goldschmidt  and  C o n s  t a m  {Jour.  Soc. 
Ghem.  Ind.,  iii.  159)  found  that  the  mixture  of  bases  extracted 
by  vitriol  from  coal-tar  boiled  between  92°  and  200°,  and  after 
repeated  fractionation  a  little  passed  over  below  100°,  and  about  one- 
half  between  114°  and  117°  (pyridine),  while  above  this  tempera- 
ture no  constant  boiling-point  was  observed.  Yery  little  distilled 
above  160°.  The  most  volatile  fraction  boiled  constantly  at  92°— 
93°,  and  was  found  to  be  a  definite  hydrate  of  pyridine, 
from  which  treatment  with  solid  caustic  potash  caused  a  separation 
of  absolute  pyridine,  boiling  at  114°— 115°. 

C.  Hausermann  has  pointed  oiit  that  the  amount  of  sul- 
phuric acid  employed  in  English  tar-works  for  treating  50  and  90 
per  cent,  benzols  is  insufficient  to  remove  the  bases.  He  found  up 
to  O'lO  per  cent,  of  pyridine  in  commercial  50  per  cent,  benzol, 
and  0'25  per  cent,  in  the  toluol  made  from  this.  Hence  the  nearly 
pure  benzene,  toluene,  xylene,  &c.,  now  largely  manufactured,  can 
be  employed  with  advantage  for  the  preparation  of  the  pyridine 
bases,  as  the  tedious  fractionation  has  already  been  accomplished. 
Thus  the  base  extracted  by  diluted  sulphuric  acid  from  toluene 
will  be  nearly  pure  pyridine ;  from  xylene,  chiefly  picoline ;  and 
from  burning  and  solvent  naphtha,  the  higher  homologues. 
English-made  toluene  yields  about  0*5  per  cent,  of  pyridine,  and  a 
similar  amount  of  picoline  can  be  extracted  from  commercial  xylene. 
Pyridine  is  more  commonly  made  from  crude  heavy  naphtha,  and 
picoline  from  the  lighter  creosote  oils. 

Pyridine. 

C5H,IT;orCH{;^^^;^g;}N 

This  body  is  the  lowest  and  most  important  member  of  the 
pyridine  series  of  bases.  It  has  been  used  as  an  antiseptic  and 
germicide,  and  is  employed  in  Germany  for  "denaturating"  alcohol. 
Pyridine  is  the  starting-point  in  the  preparation  of  several  valuable 
antipyretics,  and  many  of  the  natural  alkaloids  are  derivatives 
of  it. 


100  PROPERTIES   OF   PYRIDINE. 

The  method  of  preparing  pyridine  from  tars  has  already  been 
sufficiently  indicated.  It  may  be  obtained  by  several  interesting 
synthetical  reactions,  as  by  passing  a  mixture  of  acetylene  and  hy- 
drocyanic acid  through  a  red-hot  tube: — 2C2H2  +  CHN  =  C5H5N. 
Pure  pyridine  is  conveniently  obtained  in  small  quantity  by  dis- 
tilling nicotinic  acid  with  lime:— CgH^N.COOH-f  CaO  =  C5H5N  + 
GaCOg. 

Commercial  pyridine  may  be  purified ^  by  dissolving  200  c.c.  in 
400  c.c.  (or  a  sufficiency)  of  strong  hydrochloric  acid,  filtering  the 
liquid  if  necessary,  and  then  adding  1000  c.c.  of  a  30  per  cent, 
aqueous  solution  of  potassium  ferrocyanide.  The  precipitate  is 
filtered  off  and  washed  with  cold  water,  in  which  the  hydroferro- 
cyanides  of  ammonia  and  the  picolines  are  easily  soluble,  while  the 
corresponding  salt  of  pyridine  dissolves  but  sparingly.  The  washed 
precipitate  is  treated  with  a  cold,  highly  concentrated  solution  of 
caustic  soda,  when  the  pyridine  separates  as  an  oily  layer ;  and, 
thus  obtained,  it  contains  a  considerable  but  variable  proportion  of 
water^  but  if  desired  may  be  rendered  anhydrous  by  treatment  with 
sticks  of  caustic  potash  or  soda,  which  should  be  renewed  until 
they  cease  to  liquefy  on  standing. 

Pure  pyridine  is  a  colourless  liquid,  having  a  most  powerful  and 
persistent  odour,  and  producing  a  bitter  taste  in  the  mouth  and  at 
the  back  of  the  throat.  The  vapour  causes  severe  headache.  Pyri- 
dine has  a  specific  gravity  of  *9858  at  0°  C.,^  and  boils  at  116°*7 
according  to  Anderson,  or  115°  according  to  Thenius.  The  pre- 
sence of  water,  which  it  is  difficult  to  separate  completely,  and 
which  pyridine  absorbs  with  avidity  from  the  air,  greatly  reduces 
the  boiling-point.  Pyridine  seems  to  form  a  definite  hydrate, 
C5H5N,  SHgO,  of  specific  gravity  1'0219,  boiling  constantly  at 
92°-93°  C. 

Pyridine  dissolves  in  water  in  all  proportions,  but  is  precipitated 
from  its  solutions  by  excess  of  strong  potash  or  soda.  It  is  also 
miscible  with  alcohol,  ether,  chloroform,  benzene,  and  the  fatty  oils. 

The  effects  of  pyridine  on  animals  are  described  on  page  98. 

Pyridine  is  a  powerful  base,  neutralising  acids  completely  and 
fuming  like  ammonia  in  presence  of  hydrochloric  acid  and  other 
volatile  acids.  It  blackens  calomel,  and  precipitates  many  metallic 
solutions.     Pyridine  has  no  effect  on  a  solution  of  calcium  chloride, 

1  Pyridine  might  probably  be  advantageously  purified  from  pyrrol  and  strong- 
smelling  impurities  by  dissolving  it  in  petroleum  spirit  and  passing  hydro- 
chloric acid  gas,  the  precipitated  hydrochloride  of  pyridine  being  removed, 
pressed,  and  dried  at  a  gentle  heat. 

2  According  to  A.  Ladenberg  {Ber.,  xxi.  289),  the  specific  gravity  of 
pyridin<3»j»repai«d  from  the  mprpuro-cliloiri^ejs  .1^^)053  at  0°  0. 


DERIVATIVES  OF  PYRIDINE.  101 

but  on  passing  carbon  dioxide  through  the  liquid  calcium  carbonate 
is  precipitated.  (No  precipitate  is  produced  if  aniline  be  substituted 
for  pyridine  in  this  reaction.)  Absolute  pyridine  has  no  action  on 
litmus,  but  in  presence  of  water  it  turns  it  strongly  blue,  though 
the  reaction  is  not  capable  of  being  employed  for  titrating  the  base, 
for  which  purpose  methyl-orange  is  suitable.  On  phenolphthalein 
pyridine  has  no  action. 

Pyridine  is  an  extremely  stable  body.  It  is  unaffected  by  treat- 
ment with  chromic  or  fuming  nitric  acid,  and  these  reagents  may 
be  employed  to  free  it  from  aniline  and  empyreumatic  impurities. 

When  chlorine  is  passed  into  a  chloroformic  solution  of  pyri- 
dine, an  additive-compound,  051X5^,012,  separates  in  white  flakes. 
Bromine  forms  a  similar  unstable  compound.  A  substitution- 
product,  dibrompyridine,  OgHgBrgN,  is  formed  by  heating 
to  200°  a  mixture  of  pyridine  hydrochloride  and  bromine,  or  the 
orange-coloured  precipitate  formed  on  adding  bromine  to  a  solution 
of  pyridine  hydrochloride.  It  is  precipitated  by  adding  water  to 
its  solution  in  strong  hydrochloric  acid,  in  needles  melting  at  109° 
but  commencing  to  sublime  at  100°.  It  is  soluble  in  ether  and 
unacted  on  by  alkalies,  acids,  or  oxidising  agents. 

By  reduction  with  tin  and  hydrochloric  acid,  pyridine  is  converted 
into  piperidine,  OgHi^N,  identical  with  the  substance  obtained 
by  hydrolysis  of  piperine,  the  alkaloid  of  pepper. 

Dipyridine,  CiqH^qN^,  is  obtained  with  other  products  by  heating 
pyridine  with  sodium.  Dipyridine  is  a  base,  which  melts  at  108°, 
sublimes  at  a  higher  temperature  in  long  needles,  and  forms  a 
hydrochloride,  C-^qR^qN 2,^^.01,  the  solution  of  which  yields 
with  potassium  ferrocyanide  a  blue  precipitate  which  dissolves  in 
hot  water  to  form  a  purple  solution.-^ 

Para-dipyridylj  O5H4N.NO5H4,  formed  simultaneously  with  di- 
pyridine, is  a  base,  crystallising  in  long  needles  melting  at  114° 
and  boiling  at  305°  {Jour.  Chem.  Soc,  xliv.  483).  Both  these 
bodies  yield  iso-nicotinic  acid  on  oxidation,  while  the  iso- 
meric wefa-dipyridyl  yields  nicotinic  acid. 

Salts  op  Pyridine. 

Pyridine  forms  well-defined  salts,  most  of  which  are  crystallis- 
able  and  deliquescent.  They  are  odourless  when  pure,  and  can  be 
dried  without  change  at  100°,  but  become  slightly  coloured  on 
exposure  to  air  and  light. 

^  Iso-dipyridine,  CioHjoOg,  as  obtained  by  fractionating  the  mother-liquors 
from  the  preparation  of  dipyridine,  is  a  yellow  oil  which  does  not  solidify  in 
a  mixture  of  snow  and  salt,  even  on  addition  of  crystals  of  pyridine.  It  has  a 
specific  gravity  of  1  '08,  and  is  a  strong  base,  sparingly  soluble  in  water,  but 
miscible  in  all  proportions  with  alcohol  and  ether. 


102  SALTS  OF  PYRIDINE. 

Pyridine  Nitrate,  CgHr^NjHNOg,  forms  slender,  colourless  needles, 
or  short  thick  prisms,  very  easily  soluble  in  water,  but  less  so  in 
alcohol,  and  insoluble  in  ether. 

Pyridine  Sul2')hate,{G^^\-,^fiO^,  is  crystalline,  and  extremely 
soluble  in  water  and  alcohol.^ 

Pyridine  Hydrochloride,  C^HsISTjHCl.  When  pyridine  is  neutral- 
ised with  hydrochloric  acid,  and  the  solution  evaporated  at  100°, 
a  syrupy  liquid  is  obtained,  which,  on  cooling,  becomes  gradually 
converted  into  a  mass  of  radiating  crystals.  The  salt  deliquesces  in 
moist  air,  and  sublimes  unchanged  at  a  high  temperature.  It  is 
volatile  to  a  very  notable  extent  at  100°,  and  hence  cannot  be 
dried  at  that  temperature  without  loss.  It  is  readily  soluble  in 
water  and  alcohol,  but  insoluble  in  ether. 

With  platinic  chloride,  a  solution  of  pyridine  hydrochloride 
yields  a  yellow  crystalline  precipitate  of  the  chloroplatinate, 
(0^11^1^,1101)2^101^,  easily  soluble  in  boiling  water,  less  so  in 
alcohol,  and  insoluble  in  ether.  When  pyridine  chloroplatinate, 
free  from  excess  of  platinic  chloride,  is  boiled  with  water  for  many 
hours,  it  is  converted  into  the  hydrochloride  of  platino- 
pyridine,  CioH6PtN2,4HCl,  with  libration  of  2HC1.  The  new 
substance  is  a  sulphur-yellow,  insoluble  body,  which  evolves  jDyridine 
when  boiled  with  caustic  alkali. 

Pyridine  Picrate,  C5H5N,HC2H2(]S'02)30,  is  deposited  in  beauti- 
ful yellow  needles  when  picric  acid  in  aqueous  solution  is  added 
to  a  solution  of  an  equivalent  weight  of  pyridine.  The  salt  has  a 
remarkable  tendency  to  carry  picric  acid  down  with  it,  so  that  if 
twice  the  equivalent  proportion  of  picric  acid  be  employed,  the  pro- 
duct has  the  percentage  composition  of  an  acid  salt,  Py,2Pc;  but 
its  real  nature  is  indicated  by  its  behaviour  with  ether,  which  dis- 
solves out  the  free  jjicric  acid,  leaving  the  normal  picrate.  Pyridine 
picrate  may  also  be  prepared  by  mixing  strong  solutions  of  sodium 
picrate  and  pyridine  hydrochloride.  The  salt  melts  at  162°  C, 
and  is  soluble  in  91  parts  of  cold  water,  but  in  less  than  6  parts 
of  boiling  water.  It  is  readily  soluble  in  hot  alcohol,  but  requires 
about  100  parts  of  the  cold  solvent,  and  is  deposited  on  cooling  in 
long,  slender,  interlaced  needles  of  a  beautiful  yellow  colour.  It  is 
only  very  slightly  soluble  in  ether,  chloroform,  or  benzene,  and 
practically  insoluble  in  petroleum  spirit,  but  it  dissolves  with  great 
facility  in  pyridine  and  cresylic  acid.  It  is  readily  soluble  on 
warming  in  ether,  benzene,  or  petroleum  spirit  containing  10  per 

^  In  Waits*  Dictionary,  vol.  i.  page  755,  there  is  only  described  an  acid  sul- 
phate, which  is  said  to  be  obtained  by  evaporating  sul[)huric  acid  with  excess 
of  ^rridinfu 


PYRIDINE   COMPOUNDS.  103 

cent,  of  cresylic  acid,  and  is  freely  soluble  in  aqueous  solution  of 
pyridine  and  sodium  cresylate  (A.  H.  Allen). 

Pyridine  picrate  has  an  intensely  bitter  taste  and  nauseous  pyridic 
after-taste.  A  moderate  dose,  for  example  0*2  gramme,  produces 
violent  vomiting.     It  is  a  valuable  insecticide. 

Pyridine  is  remarkable  for  its  tendency  to  form  compounds  with 
metallic  salts.  These  bodies  are  more  or  less  liable  to  decomposi- 
tion by  washing  or  boiling  with  water,  and  lose  pyridine  when 
heated  to  100°,  or  a  somewhat  higher  temperature.  The  zinc 
chloride  compound,  ZnGlg.SCgHgN,  separates  as  a  voluminous 
white  precipitate  on  treating  an  aqueous  solution  of  zinc  chlo- 
ride with  excess  of  pyridine.  It  crystallises  from  water  in  long, 
white  silky  needles,  which,  when  repeatedly  washed,  or  boiled  with 
water,  decompose  into  pyridine  and  a  basic  zinc  chloride.  The 
zinc  chloride  compound  dissolves  in  hydrochloric  acid  to  form  a 
double  chloride  of  zinc  and  pyridine,  ZnCl2,(C5H5N,HCl)2,  which 
forms  groups  of  white  lustrous  needles.  Cadmium  chloride 
behaves  with  pyridine  in  a  manner  similar  to  zinc  chloride,  the 
compound  formed,  CdCJg.SCgHgN,  crystallising  in  needles  and 
being  partially  decomposed  by  a  large  quantity  of  water.  The 
cupric  chloride  compound  is  precipitated  in  fine  greenish 
silky  needles  on  adding  pyridine  to  an  alcoholic  solution  of  cupric 
chloride.  It  is  soluble  in  pyridine,  in  aqueous  solutions  of  pyridine, 
and  in  ammonia.  With  mercuric  chloride,  a  very  dilute 
aqueous  solution  of  pyridine  (1-1000)  yields  a  precipitate  which 
dissolves  extremely  easily  in  warm  water,  and  separates  out,  as  the 
solution  cools,  in  long  white  needles.  With  mercuric  iodide, 
pyridine  forms  a  compound  which  crystallises  from  alcohol  in 
beautiful  white  needles. 

Prom  acid  solutions  of  pyridine,  phosphotungstic  acid  throws 
down  a  very  difficultly  soluble  precipitate. 

Detection  and  Determination  of  Pyridine. 

The  recognition  and  determination  of  pyridine  are  to  a 
great  extent  based  on  the  properties  and  reactions  already  de- 
scribed. In  the  free  state,  the  smell  and  basic  character  of 
pyridine  amply  suffice  for  its  recognition  in  the  absence  of  other 
basic  substances  of  powerful  odour,  and  it  is  readily  liberated 
from  its  salts  by  addition  of  caustic  soda,  and  obtained  free 
from  every  interfering  substance  by  distilling  its  aqueous  solu- 
tion. It  may  also  be  extracted  from  its  aqueous  solution  by 
agitation  with  ether,  provided  that  the  liquid  be  saturated  with 
caustic  soda. 

In  the  absence  of  ammonia,  or  other  bases,  free  pyridine  may  be 
determined  by  titration  with  standard  acid  and  methyl-orange  (not 


104  DETECTION  OF   PYRIDINE. 

litmus).  1  c.c.  of  normal  acid  neutralises  0*079  gramme  of  pyri- 
dine. 

From  aniline,  pyridine  is  distinguished  by  not  giving  any  coloured 
product  on  adding  a  solution  of  bleaching  powder,  though  the  liquid 
acquires  a  new  and  peculiar  odour. 

The  presence  of  ammonia  in  pyridine  can  be  recognised  (in  the 
absence  of  fixed  alkalies)  by  the  red  coloration  produced  in  the 
aqueous  solution  by  phenol-phthalei'n,  on  which  pure  pyridine  has  no 
action.  If  the  indicator  be  used  in  considerable  quantity,  and  a 
low  temperature  employed  (as  recommended  by  J.  H.  Long, 
Analyst,  xv.  53),  the  ammonia  can  be  approximately  determined 
by  titrating  the  aqueous  solution  with  standard  acid. 

K.  E.  Schulze  recommends  ferric  chloride  as  an  indicator  (see 
page  106).  According  to  W.  Lang,  the  traces  of  pyridine  some- 
times contained  in  commercial  alcohol  may  be  detected  and  removed 
by  shaking  the  spirit  with  powdered  zinc  chloride ;  or,  according 
to  W.  K  i  r  s  c  h  m  a  n  n,  by  the  addition  of  an  acid  solution  of 
aluminium  sulphate.  In  the  former  case,  the  pyridine  is  removed 
in  the  form  of  its  zinc  chloride  compound,  and  in  the  latter  case 
pyridine  alum  is  formed. 

The  traces  of  pyridine  sometimes  present  in  fusel  oil  may  be 
detected  by  adding  picric  acid,  which  occasions  a  formation  of 
pyridine  picrate. 

For  the  detection  of  traces  of  pyridine  in  commercial  ammonia, 
H.  0  s  t  recommends  that  the  sample  should  be  nearly  neutralised, 
when  the  odour  of  pyridine  may  be  recognised.  By  distilling  the 
nearly  neutralised  liquid,  collecting  the  distillate  in  hydrochloric 
acid,  evaporating,  and  extracting  the  residue  with  absolute  alcohol, 
a  solution  is  obtained  containing  but  little  ammonium  chloride. 
What  is  present  is  removed  by  boiling  off  the  alcohol  and  adding 
platinic  chloride  solution,  when,  on  evaporating  the  filtrate  and 
adding  alcohol,  the  pyridine  chloroplatinate  crystallises 
in  smooth,  ramifying,  orange-red  prisms,  readily  soluble  in  boiling, 
but  very  sparingly  in  cold,  water. 

Commercial  Pyridine,  as  now  produced,  consists  chiefly  of 
pyridine  and  picoline.  Ammonia  is  apt  to  be  present 
in  notable  quantity,  as  also  pyrrol  and  other  strong  smelling 
impurities.^  A  considerable  but  variable  proportion  of  w  a  t  e  r 
is  present. 

Pyridine  is  employed  in  Germany,  in  conjunction  with  wood 

*  The  pyridine  produced  at  certain  works  becomes  turbid  when  diluted  with 
more  than  40  per  cent,  of  water,  whereas  the  best  makes  are  miscible  with 
water  in  all  proportions.  On  distilling  the  former  brands  the  disturbing  im- 
purity is  left  in  the  '*  tailings." 


ASSAY   OF   PYRIDINE.  105 

spirit  and  turpentine,  for  "  denaturating"  spirit.  An  article  intended 
to  be  used  for  this  purpose  is  required  to  answer  to  the  following 
official  tests. 

1.  The  colour  must  not  be  deeper  than  straw-yellow.  2.  If 
1  c.c.  of  the  sample  be  dissolved  in  250  c.c.  of  distilled  water,  and 
20  c.c.  of  the  resultant  solution  be  treated  with  a  5  per  cent,  aqueous 
solution  of  cadmium  chloride,  a  distinct  turbidity  should  appear  in 
a  few  moments.^  3.  When  100  c.c.  of  the  sample  is  distilled  (in 
a  small  metal  flask  provided  at  the  top  with  a  small  globe,  which 
is  connected  with  a  Liebig's  condenser,  a  thermometer  being  fitted 
to  the  globe,  and  a  moderate  heat  applied)  so  that  the  distillate 
passes  over  in  separate  drops,  90  per  cent,  should  have  distilled 
when  the  thermometer  stands  at  140°  C.  4.  When  the  sample  is 
mixed  with  twice  its  measure  of  water  it  must  wholly  dissolve,  and 
no  oily  drops  must  separate  even  after  long  standing.  5.  Four  drops 
of  the  sample  heated  on  platinum  foil  over  a  Bunsen  burner  should 
burn  with  a  sooty  flame,  and  leave  no  residue.  6.  When  20  c.c. 
of  the  sample  is  shaken  with  an  equal  measure  of  a  solution  of  caustic 
soda  of  1  '4  specific  gravity,  a  layer  of  anhydrous  bases,  measuring 
at  least  18  c.c.  (  =  90  per  cent.),  should  separate  out  on  standing. 

The  last  test  is  now  usually  replaced  by  one  prescribing  the  use  of 
solid  caustic  potash.  50  c.c.  measure  of  the  sample  is  placed  in  a 
graduated  cylinder,  furnished  with  a  stopper,  and  a  long  stick  of 
potash  immersed  in  it.  The  alkali  gradually  absorbs  the  water 
from  the  pyridine,  and  forms  a  lower  layer  of  saturated  solution. 
A  second  stick  is  added  as  soon  as  the  first  has  sunk  much  below 
the  surface  of  the  pyridine,  and  is  followed  by  a  third  if  the  second 
liquefies  completely  or  considerably.  Agitation  should  be  avoided, 
and  care  must  be  taken  that  the  last  stick  is  left  in  contact  with 
the  upper  layer  of  bases  until  the  action  is  at  an  end.  It  is  then 
cautiously  removed  with  a  bent  wire,  or  broken  down  by  a  glass 
rod,  and  the  volume  of  the  layer  of  anhydrous  bases  carefully 
observed.  By  this  test,  commercial  pyridine  usually  shows  from  8 
to  10  per  cent,  of  water  (  =  92  to  90  per  cent,  of  anhydrous  bases). 

Instead  of  determining  the  water,  K.  E.  Schulze  recommends 
titration  of  the  bases  with  standard  acid.  For  this  purpose  5  c.c. 
of  the  sample  should  be  dissolved  in  water,  and  the  solution  diluted 
to  100  c.c.  To  20  c.c.  of  this  solution  (=1  c.c.  of  the  sample)  is 
added  1  c.c.  of  a  5  per  cent,  aqueous  solution  of  ferric  chloride. 

*  "Wepper  and  Liiders  {Jour.  Soc.  Chem.  Ind.,  vii.  762)  have  pointed 
out  the  unreliable  character  of  this  test,  which  they  attribute  to  the  varying 
composition  of  cadmium  chloride.  Of  two  samples  of  the  salt,  only  one  gave 
the  reaction  with  pyridine.  They  recommend  the  employment  of  a  stronger 
solution  of  the  pyridine  than  that  prescribed  in  the  test. 


106  PIPERAZINE. 

Normal  sulphuric  acid  is  then  run  in  slowly  with  agitation,  till  the 
precipitated  ferric  hydroxide  is  redissolved.  1  c.c.  of  normal  acid 
(containing  49  grammes  of  HgSO^  per  litre)  corresponds  to  '079 
gramme  of  pure  anhydrous  pyridine,  or  to  '095  gramme  of  picoline. 
Pyridine  intended  for  pharmaceutical  or  medicinal  use  should 
not  be  altered  by  light ;  a  1 0  per  cent,  solution  in  water  should 
not  be  reddened  by  phenol-phthalein  (presence  of  ammonia) ;  and 
5  c.c,  to  which  2  drops  of  decinormal  permanganate  have  been 
added,  should  retain  a  red  colour  for  at  least  an  hour. 

Piperidine.    C5HiiN  =  C5H,(H5)NH. 

This  body  has  the  constitution  of  a  pyridine  hexa- 
hydride.^  It  is  obtained  by  the  reduction  of  pyridine  by  nascent 
hydrogen.  The  following  formulae  show  the  relation  of  pyridine  to 
piperidine  and  piperazine:^ — 

ch{SSSS:}^^    ch4:Ch.ch.}^h    hn{;Ch.ch.|kh 

Pyridine.  Piperidine.  Piperazine. 

Piperidine  is  also  obtained  by  rapidly  heating  pentamethylene- 
diamine  (amylene-diamine)  hydrochloride  : — 

C5Hio(NH2)2.HCl  -  CgHiiN  +  NH.Cl . 

Piperidine  is  also  produced  by  the  hydrolysis  of  piperine, 
CigHjgNOg,  the  alkaloid  of  pepper,  which,  on  boiling  with  alkalies, 
splits  into  piperidine  and  pip  eric   acid:^ — 

Ci,Hi,N03+H,0  =  C,HuN  +  Ci,Hi„0, . 

Piperidine  is  a  colourless  limpid  liquid,  of  peculiar  odour,  re- 
sembling at  the  same  time  that  of  pepper  and  ammonia,  and  has 

^  Pyridine  di-and  tetra -hydrides  and  their  homologues  are  capable  of  existing 
theoretically.  The  latter  class,  called  piperideins,  have  been  prepared  by 
the  action  of  caustic  soda  and  bromine  on  the  piperidines  {Ber.,  xx.  1645). 

2  Piperazine  or  Piperazidine is  probably  identical  with  diethylene- 
diamine.  It  is  a  strong  base,  molting  at  104°-107°,  boiling  at  135°-138°, 
and  absorbiog  carbon  dioxide  from  the  air.  Piperazine  has  neither  caustic  nor 
toxic  properties,  and  passes  through  the  system  unchanged,  but  dissolves  uric 
acid  in  large  amount,  forming  the  neutral  urate,  C4HioN2,C5H4N408. 
Piperazine  phosphate  forms  four-sided  tabular  crystals,  which  character,  and 
those  of  the  bismutho-iodide,  distinguish  piperazine  from  spermine, 
C4H8N2,  which  otherwise  it  closely  resembles. 

'  A  small  quantity  of  piperidine  is  said  to  be  obtained  on  distilling  pepper 
with  water  alone,  probably  owing  to  partial  decomposition  of  the  piperine  by 
water  or  a  ferment  (W.  Johnstone,  Analyst,  xix.  46). 


PIPERIDINE.  107 

a  very  caustic  taste.  It  boils  and  distils  unchanged  at  106°,  and 
dissolves  in  all  proportions  in  water  and  alcohol.  When  piperidine 
is  treated  with  water  heat  is  evolved. 

Piperidine  is  a  powerful  base.  Its  aqueous  solution  restores  the 
blue  colour  of  reddened  litmus-paper,  and  behaves  like  ammonia 
with  metallic  solutions,  except  that  the  precipitates  produced  with 
salts  of  zinc  and  copper  are  not  soluble  in  excess.  Piperidine 
absorbs  carbon  dioxide  from  the  air,  and  if  the  gas  be  passed  into 
a  solution  of  calcium  chloride,  to  which  piperidine  has  been  added, 
calcium  carbonate  is  precipitated.  Piperidine  may  be  estimated  by 
titration  with  standard  acid,  using  either  litmus  or  methyl-orange 
as  an  indicator. 

Piperidine  forms  a  series  of  readily  crystallisable  salts,  most  of 
which  are  soluble.  The  cliloroplatinate^  {C^-^^)^^iG\Q,  forms 
orange  needles,  very  soluble  in  water,  but  less  so  in  alcohol. 

Piperidine  is  a  secondary  amine.  When  dropped  into  cooled  methyl 
iodide  it  forms  the  compound  CgH^oC^-^s)-^'^-'^-  When  distilled 
with  alkali  this  yields  the  free  base  methylpiperidine,  which, 
when  heated  under  pressure  with  methyl  iodide,  gives  the  iodide 
of  dimethyl-piper ylene-ammonium,  C5Hjq(CH3')2NI. 

The  homologues  of  piperidine  are  called  by  Ladenburg 
pipecolines,  C5Hio(CH3)N,  lupetidines,  C5H9(CH3)2N,  copellidines, 
C,H3(CH3)3N,  &c. 

Piperidine  is  closely  related  to  a  number  of  the  natural  alkaloids 
besides  piperine,  as  will  be  seen  from  the  following  formulae : — 

Conine.         Dextro-a-normal-  )         .^^   (  CH2.CH(C3Hy)  )  ^^t 
propyl-piperidine.  J         ^^2|cH2.CH2  J^^ 

CoNHYDRiNE.       Probably  hy-  |  ^„    (  CH2.CH(0H)  "(  ^j.^  ^  . 
droxy-conine.  |   ^^2 1  CH2.CH2  |  ^(^sHy) 

Tropine.       Methyl-a-hy-   )  ,  ^^  ^    ,^  .  . 

droxyethyl-  tetrahydro-    I GR^  \  ^^2^^{^2^a^^)  I  jsf  (CH3) 
pyridine.  J 

KicoTiNE.     Hexahydro-dipyridyl.  C6H4(H3)N.]Sr(H3)C6H^ 

Homologues  of  Pyridine. 

The  homologues  of  pyridine  occur  with  that  base  in  the  products 
of  the  distillation  of  bones,  coal,  &c.  Various  members  of  the 
class  have  been  obtained  synthetically. 

PicoLiNES.     Methyl-pyridines.    CgH^N;  or  C5H4(CH3)N. 

Three  isomeric  modifications  of  picoline  exist,  dififering  according 
to  the  orientation  of  the  CHg  group  in  relation  to  the  'N,     The  pico- 


108  METHYL-PYRIDINES. 

line  of  coal-tar  is  chiefly  the  ortho-modification  (1  : 2),  often  called 
a-picoline,  mixed  with  some  meta-  or/3-picoline  (1  : 3).^ 
Although  the  former  boils  at  134°  (Weidel ;  129°-130°,  Lange),  and 
the  latter  at  140°,  they  cannot  be  separated  by  fractional  distil- 
lation, but  may  be  isolated  by  taking  advantage  of  the  different 
solubilities  of  their  chloroplatinates  (Ber.^  xii.  2008).  Lange 
{Ber.,  xviii.  3436)  thinks  that  a-picoline  is  preferably  separated 
from  bone-oil  by  means  of  its  sparingly  soluble  mercuro-chloride. 
Its  specific  gravity  at  0°,  compared  with  water  at  4°,  is  stated  to 
be  0*9656.  The  platinochloride  melts  at  178°,  the  mercuro- 
chloride  at  167°,  and  the  picrate  at  165°.  The  two  last  salts  are 
moderately  soluble  in  water.  y-picoline(l:4)is  produced  by 
the  distillation  of  acrolein-ammonia,  or  by  heating  allyl  tribromide 
with  ammonia,  and  by  the  reaction  of  pyridine  on  methyl  iodide. 
Its  presence  has  been  recognised  in  coal-tar.  y-picoline  is  stated 
by  A.  La  d  e  nb  u  rg  {Ber.,  xxi.  285)  to  boil  at  142°-5-144°-5,  the 
specific  gravity  being  0*9742  at  0°  C.  The  platinochloride  melts 
with  decomposition  at  231°;  the  aurochloride  at  205°;  the  mer- 
curo-chloride at  128°-129°  ;  and  the  picrate  at  167°.  These  char- 
acters are  not  strictly  in  accordance  with  the  observations  of  Lange 
{Ber.,  xviii.  3436). 

The  picolines  are  metameric  with  aniline,  CgHg.NHg,  which, 
however,  is  a  primary  amine,  whereas  the  picolines  have  the  char- 
acters of  tertiary  bases.  In  their  odour,  solubility,  basic  properties, 
and  characters  of  their  salts,  the  picolines  closely  resemble  their 
lower  homologue  pyridine,  but  have  a  lower  density  and  higher 
boiling-point  than  the  latter  body, 

LUTIDINBS.       C7H9K 

The  bases  of  this  formula  may  have  the  constitution  of  ethyl- 
pyri dines,  C5H4(C2H5)N,  or  of  dimethyl-pyridines, 
C5H3(CH3),N. 

1  :  4  or  y-e thy  1-pyri dine  constitutes  the  greater  part  of 
coal-tar  lutidine.  It  is  a  colourless  liquid  of  '9443  specific  gravity 
at  0°,  boiling  at  154°,  and  miscible  with  cold  water  in  all  propor- 
tions.    By  oxidation  it  yields  iso-nicotinic  acid. 

^  A.  Ladenburg  {Ber.,  xxiii.  2688)  aflfirms  the  existence  of  two  )8-pico. 
lines;  the  variety  from  glycerol  boiling  at  141°*5-142°  (uncorrected),  and  that 
from  strychnine  at  146°-149°  (uncorrected).  C.  Stoehr  {Ber.,  xxiii.  3151) 
disputes  Ladenburg's  conclusions,  and  states  that  the  product  obtained  by  the 
distillation  of  brucine  or  strychnine  is  not  homogeneous.  After  purification  it 
yields  ^S-methyl-pyridine  boiling  at  142°-143°,  identical  with  the  synthetical 
product  obtained  by  heating  glycerol  with  acetamide  and  phosphoric  anhydride, 
which  also  contains  pyridine  and  )8-ethyl-pyridine.  The  mercuro-chloride  melts 
at  145°-146°,  and  the  chloroplatinate  at  201°-202°.     (See  Ber.,  xxiv.  1676.) 


LUTIDINES   AND   COLLIDINES. 


109 


A  ^-ethyl-pyridine  is  formed,  together  with  its  lower  homo- 
logues,  by  heating  glycerol  with  acetamide  and  phosphoric  anhy- 
dride (C.  Stoehr,  Jour.  Prac.  (7/iem.,  [3],  xliii.  153).  It  boils 
at  140°-145°,  has  a  specific  gravity  at  ^^  of  "9751,  is  almost 
insoluble  in  water,  and  yields  nicotinic  acid  on  oxidation. 

Three  isomeric  dimethyl-pyridines  have  been  found  by 
Rosenberg  in  vitriol-tar.  Of  these,  the  1:2:6  {a-a)  isomeride  is 
a  colourless  oil  boiling  at  142°— 143°,  and  having  a  penetrating 
odour  resembling  that  of  oil  of  peppermint.  It  is  freely  soluble  in 
cold,  but  less  so  in  hot  water.  The  1:2:4  (a-y)  isomer  boils 
at  157°.  The  1:2:3  (a-/3)  modification  has  not  been  isolated, 
but  its  presence  is  inferred  from  its  product  of  oxidation,  iso- 
cinchomeronic  acid. 

Hanzsch  (Annalen,  ccxv.  1)  has  described  a  lutidine 
(C5H3(CH3)2N)  boiling  at  154°,  obtained  by  distilling  a  mixture  of 
lutidine-tricarboxylate  with  lime.  A  lutidine,  apparently  having 
the  constitution  /3,8-dimethyl-pyridine,  has  been  prepared  by 
D  U  r  k  0  p  f  and  G  d  1 1  s  c  h  (Ber.,  xxiii.  1113)  by  eliminating  COg 
from  a  dimethyl-pyridine-carboxylic  acid  obtained  by  the  oxidation 
of  a  parvoline  boiling  at  216°-217°.  It  boils  at  169°-170°, 
has  a  feeble,  not  unpleasant  odour,  and  dissolves  sparingly  in  cold, 
but  readily  in  boiling  water.  The  specific  gravity  at  ^/^  is  0*9614. 
The  mercuro-chloride  crystallises  in  long  sparingly  soluble  needles, 
melting  at  170°.  On  oxidation  it  yields  a  pyridine-dicarboxylic  acid 
melting  at  314°-315°,  from  which  fact,  and  its  external  characters, 
the  authors  infer  it  to  be  dinicotinic  acid. 

COLLIDINES.       CgHj^N. 

A.  Hanzsch  (Annalen,  ccxv.  1  ;  Jour.  Ghem.  Sac,  xliv.  82) 
gives  the  following  description  of  the  two  known  modifications  of 
collidine : — 


a-Collidine. 

Methyl-ethyl-pyridine. 

CsHgiCflaXCaHs)!?. 

/3-Collidine. 
j3-trimethyl-pyridine. 

C5H2(CH3)3N. 

Boiling-point, 

,  Specific  gravity  at  15°,    .    . 

SolubiUty  in  water,   .    .    . 

Behaviour  on  exposure  to 

air, 
C8HiiN,HAuCl4,    .... 

Addition  of  CrOs  gives  .    . 

Mn,  Co,  and  ¥e  salts,     .    . 

AgNOa 

178' 

'8fi3 
Very  slight. 
Unchanged. 

Does  not  melt  under  water. 
Red  oil 
No  precipitate. 
No  precipitate. 

171° 

■917 

More  readily  soluble  in  cold 

than  hot. 
Becomes  brown. 

Melts  under  hot  water  ;  the 
dry  salt  melts  at  112°. 

Red  crystalline  precipitate 
of  (C8HiiN)2H2Cr207. 

Hydroxides  gradually  pre- 
cipitated. 

White  crystalline  precipi- 
tate soluble  in  hot  water. 

110  COLLIDINES. 

0.  de  Goninck  has  described  a  ^-collidine  boiling  at  195°- 
196°  {Gompt  Rend.,  xci.  296  ;  xcv.  298),  having  a  specific  gravity 
of  '9656  at  0°;  and  another  modification,  stated  to  be  a  trimethyl- 
pyridine,  has  been  isolated  by  J.  Mohler  {Ber.^  xxi.  1006  ;  Joiir. 
Chem.  Soc,  liv.  727)  by  subjecting  the  bases  from  coal-tar  to  frac- 
tional precipitation  with  potassium  ferrocyanide.  It  is  a  colourless 
liquid,  unchanged  by  exposure  to  air,  soluble  slowly  but  to  a 
considerable  extent  in  cold  water,  and  separating  again  almost 
completely  on  warming.  The  hydrochloride  forms  slender  non- 
deliquescent  needles,  which  sublime,  without  melting,  with  partial 
decomposition.  The  sulphate  forms  transparent  prisms  melting  at 
203°,  and  the  picrate  long,  silky  needles  melting  at  155°-156°. 

Pyridine-Carboxylic  Acids. 

Pyridine  itself  is  an  extremely  stable  body,  resisting  the  strongest 
oxidising  agents ;  but  its  homologues  yield  by  oxidation  a  series  of 
acids  in  which  the  alkyl-groups  are  replaced  by  a  corresponding 
number  of  carboxyl-groups.  The  pyridine-carboxylic  acids  derive 
their  chief  interest  from  the  light  they  throw  on  the  relationship 
of  the  natural  vegetable  alkaloids  to  the  pyridine  bases.  Three  iso- 
meric pyridin  e-mono  car  boxy  lie  acids,  CgH^N.COOH, 
are  obtainable,  exactly  corresponding  to  the  three  isomeric  modifica- 
tions of  picoline  (methyl-pyridine).i  The  same  acids  may  also  be 
obtained  by  the  action  of  heat  on  the  di-  or  tri-carboxylic  acids, 
just  as  benzoic  acid,  CgHg.COOH,  is  obtained  by  the  action  of  heat 
(and  lime)  on  phthalic  acid,  CgH^.(C00H)2.  One  of  them  (nico- 
tinic acid)  is  also  obtained  by  the  action  of  heat  on  nicotine. 

Ptridine-monocarboxylio  Acids,  CgH^KCOOH,^  unite  in 
themselves  the  basic  characters  of  pyridine  with  those  of  an  acid. 
Thus  they  combine  with  hydrochloric  acid,  and  the  resulting  com- 

^  The  pyridine-monocarboxylic  acids  have  the  empirical  formula  CgHgNOg, 
and  the  same  percentage  composition  as  nitro  benzene. 

2  The  bases  from  coal-tar  boiling  between  130°  and  140"  are  boiled  in  an 
apparatus  furnished  with  a  reflux  condenser  with  ten  times  their  weight  of  potas- 
sium permanganate  in  2^  per  cent,  aqueous  solution,  until  the  permanganate  is 
reduced.  The  oxide  of  manganese  is  then  filtered  off,  and  the  clear  liquid  con- 
centrated to  a  small  bulk.  It  is  then  neutralised  and  treated  with  acetate  of 
copper.  The  precipitate  is  separated,  decomposed  by  sulphuretted  hydrogen, 
and  the  filtrate  decolorised  by  animal  charcoal.  On  further  concentration  and 
cooling  it  deposits  colourless  needles  of  picolinic  acid.  The  filtrate  from 
the  copper  precipitate  is  further  evaporated,  acidulated  with  acetic  acid,  and 
treated  at  its  boiling-point  with  acetate  of  copper.  The  resulting  bluish-green 
precipitate  is  separated,  boiled  rapidly  with  water,  and  decomposed  by  sul- 
phuretted hydrogen.  On  evaporation,  the  filtrate  deposits  colourless  crusts  of 
isonicotinic  acid. 


PYRIDINE-CARBOXYLIC   ACIDS. 


Ill 


pound  forms  double  salts  with  mercuric  chloride,  platinic  chloride, 
&c. ;  while,  on  the  other  hand,  they  form  a  series  of  well-defined 
crystallisable  salts.  The  following  table  exhibits  their  more  im- 
portant characters : — 


Ortho-  Compound 

or  a- Acid. 
Picolinic  Acid. 


Meta-Compound 

or  P-Acid. 
Nicotinic  Acid. 


Para-  Compound 

or  y-Acid. 
Isonicotinic  Acid. 


Mode  of  formation, 


Crystalline  character,    . 
Melting-point, 

Solubility,      .       .       . 


Reaction  with   neutral 
lead  acetate, 

Reaction      with      am- 
moniacal  lead  acetate, 

Reaction    with    cupric 
acetate, 


Reaction   with    ferrous 
sulphate. 

Characters     of     hydro- 
chloride— 

C6H5N02,HC1, 


Oxidation  of  a- 
picoline  by  per- 
manganate. 


Prismatic  needles. 


135';   sublimes  in 
lustrous  needles. 


Easily  soluble  in 
cold  or  hot  water 
and  in  alcohol. 
Nearly  insoluble 
in  ether,  chloro- 
form, benzene, 
&c. 

No  change. 


No  change. 


Slowly  deposits 
shining  laminae 
and  needles  of 
violet-blue  col- 
our, and  metal- 
lic lustre.  Sol- 
uble in  hot 
water. 

Pale  reddish-yel- 
low coloration. 

Large,  lustrous, 
ortho-rhombic 
prisms,  which 
become  rapidly 
turbid  on  ex- 
posure to  air. 


Oxidation  of  /3- 
picoline  by  per- 
manganate, or 
nicotine  by  per- 
manganate 
chromic  acid  or 
nitric  acid. 

Needles. 

229'-231'. 


Sparingly  soluble 
in  cold,  easily 
in  warm  water; 
sparingly  in 
ether  or  chloro- 
form. 


Action  of  heat  on 
pyridine  di-  or 
tri  -  carboxylic 
acid.  Oxidation 
of  y-picoline. 


Needles. 


(299')   (809*); 
■    tab- 


305' 
sublime's  in 
ular  crystals. 

Sparingly  soluble 
in  water;  very 
sparingly  in 
ether  and  beii- 


No  change. 


White  crystalline 
precipitate. 

Pale  blue-green 
precipitate,  in- 
soluble in  a 
large  quantity 
of  water. 


No  change. 


Monoclinic  prisms, 
quite  permanent 
in  the  air. 


Green  precipitate 
on  warming. 


No  change. 


Large  shining  crys- 
tals. 


On  heating  with  lime,  the  above  acids  yield  pyridine,  just  as 
benzoic  acid  yields  benzene  under  similar  conditions.  The  sodium 
salts  of  the  a  and  fi  acids,  when  treated  in  solution  with  sodium 
amalgam,  give  ofif  ammonia,  and  yield  the  salt  of  an  unsaturated 
acid  of  the  fatty  series,  CgHgOg. 

Pyridine-dicarboxylio  Acids.  05X13(00011)2.  Of  the  six 
possible  acids  of  this  formula,  all  are  known.  They  are  pro- 
duced by  the  oxidation  of  homologues  of  pyridine  containing  two 


112  PYRIDINE-DICARBOXYLIC   ACIDS. 

substituted  hydrogen  atoms,  and  also  by  the  oxidation  of  other 
substances. 

QuinoUnic  Acid  [the  a-y8  modification]  is  obtained  by  the  oxida- 
tion of  coal-tar  quinoline  by  permanganate,  and  is  the  analogue  of 
phthalic  acid,  obtained  similarly  by  the  oxidation  of  nai)hthalene. 
It  crystallises  in  short  prisms,  slightly  soluble  in  cold  water, 
more  readily  in  hot  water  and  alcohol,  insoluble  in  benzene. 
It  blackens  when  heated,  and  melts  at  about  228°,  apparently 
being  converted  into  nicotinic  acid  {Jour.  Chem.  Soc,  xliv.  90). 
The  acid  is  removed  from  its  aqueous  solution  by  ether. 

Lutidinic  Add  [a-y]  is  similarly  produced  by  the  action  of 
permanganate  on  cinchonine-quinoline.  It  melts  at  235°  (219°), 
forming  iso-nicotinic  acid,  is  sparingly  soluble  in  cold  water,  and 
gives  with  cupric  acetate  a  pale  blue  precipitate.  (See  Berichte, 
XX.  127.) 

Dlpicolinic  Acid  [a-a']  melts  at  226° ;  Isocinchomeronic  Acid 
[a-p]  at  236°;  and  Dinicotinic  Acid  [/?-^']  at  323°. 

Cinchomeronic  Acid  [/J-y]  is  the  chief  product  of  the  oxida- 
tion of  quinine  by  nitric  acid,  and  is  also  obtained,  together 
with  other  products,  by  the  similar  treatment  of  cinchonine.  It 
crystallises  in  white  prismatic  needles,  which  melt  at  259°  (267°), 
with  partial  decomposition,  and  is  only  very  sparingly  soluble, 
even  in  boiling  water.  It  forms  two  classes  of  salts.  Its  most 
characteristic  reaction  is  its  behaviour  with  cupric  acetate,  which 
does  not  give  a  precipitate  in  the  cold,  but  on  heating  the  liquid 
becomes  turbid,  clearing  again  on  cooling.  On  prolonged  boiling, 
a  permanent  azure-blue  precipitate  is  formed. 

All  the  dicarboxylic  acids  which  contain  a  carboxyl-group  in  the 
a-position  give  a  reddish  yellow  coloration  with  ferrous  sulphate. 

Pyridine-tricarboxylic  Acids,  C5H2(C0.0H)3,  are  obtained  by 
the  oxidation  of  certain  alkaloids.  Thus  quinine,  quinidine,  and 
cinchonidine,  by  boiling  with  an  alkaline  solution  of  permanganate, 
yield  liydroxycinchomeronic  acid,  which  forms  orthorhombic  prisms 
melting  (with  blackening)  at  244°  ;  while  berberine,  when  oxidised 
by  nitric  acid,  yields  the  isomeric  body  berberonic  acid,  crystallis- 
ing in  the  triclinic  system.  Both  acids  give  a  deep  red  colour  with 
ferrous  sulphate,  destroyed  by  a  mineral  acid. 

Pyridine-tetracarboxylio  Acids,  C5lI]Sr(CO.OH)4,  have  been 
obtained. 

Pyrtdine-pentacarboxylio  Acid,  C5N(C0.0H)5,  forms  crystals 
containing  2  aqua.  It  becomes  anhydrous  at  120°,  and  decom- 
poses without  melting  at  220°.  It  is  freely  soluble  in  water,  and 
is  a  strong  acid,  resembling  oxalic  acid  in  its  power  of  form- 
ing acid  and  double  salts  (Hanzsch,  Jour,  Chem.  Soc,  xliv.  85). 


PYRROL. 


113 


Pyrrol.^     C^H^N,  or  C^H^.NH. 

This  associate  of  the  pyridine  bases  ^  is  a  colourless  liquid  of 
pungent  taste,  and  odour  like  that  of  chloroform.  The  specific 
gravity  is  1*077,  and  boiling-point  130°-133°.  It  is  but  little 
soluble  in  water,  and  insoluble  in  alkalies,  but  dissolves  in  dilute 
acids,  alcohol,  and  ether.  It  is  indifferent  to  most  reagents,  but 
appears  to  possess  feebly-marked  basic  properties.  The  only  definite 
salt  is  the  picrate,  which  forms  unstable  red  needles  melting  at  71°. 

Pyrrol  turns  brown  in  the  air,  and  when  warmed  with  acids 
forms  a  red  substance  known  as  pyrrol-red,  the  reaction 
apparently  occurring  being: — 3C4H5N'-}-H20  =  Ci2Hi4N20-hNH3. 
A  piece  of  pine- wood,  moistened  with  hydrochloric  acid  and  exposed 
to  the  vapour  of  pyrrol,  becomes  deep  red. 

When  a  cold  aqueous  solution  of  isatin  is  treated  with  pyrrol 
and  a  little  dilute  sulphuric  acid,  a  heavy  blue  precipitate, 
resembling  indigo,  is  obtained.  When  both  reagents  are  dis- 
solved in  glacial  acetic  acid  and  boiled,  a  deep  blue  solution  is 
obtained,  apparently  containing  the  same  colouring-matter. 

If  a  solution  of  phenanthrene-quinone  in  acetic  acid  be  treated 
with  pyrrol  and  a  little  dilute  sulphuric  acid,  a  brown  precipitate 
is  formed,  which  dissolves  in  chloroform  with  a  beautiful  violet- 
red  colour.  When  an  aqueous  solution  of  benzo-quinone  is  treated 
with  pyrrol  and  dilute  sulphuric  acid,  a  dark  green  precipitate 
is  formed,  insoluble  in  ether.  These  reactions  indicate  the  close 
relationship  between  pyrrol  and  thiophene,  which  itself  has 
the  constitution  of  a  thio-furfuran.  Many  of  the  reactions 
of  pyrrol  are  also  produced  by  carbazol,  which  is  an  i m i d o - 
diphenyl.  Indole  has  a  constitution  between  pyrrol  and 
carbazol.     Thus : — 


Pyrrol,  C4H6N. 

.CH:CH. 


{:C1;C^:}-     { 


.CH:CH 

Furfuran,  C4H4O 

.CH:CH 
.CH:CH 

Thiophene,  C4H4S. 

'.CH:CH 


Indole,  CgHyN. 

.CH:CH.  K^jj 


{: 

Th 

{: 


CH:CH. 


4U. 


Carbazol,  C12H9N.  ] 
Diphenylene  Oxide. 


Thioiiaphthene,  CgHgS. 

s 


-  Pyrrol  has  been  obtained  synthetically  by  passing  acetylene  and  ammonia 
through  a  red-hot  tube,  and  also  by  the  dry  distillation  of  the  ammonium  salts 
of  mucic  and  saccharic  acids. 

'  The  proportion  of  pyrrol  contained  in  coal-tar  is  very  small.  It  is  best 
Drepared  by  shaking  bone-oil  with  dilute  sulphuric  acid  and  fractionating 
the  insoluble  portion.  The  fraction  boiling  between  100°  and  150°  is  heated 
VOL.  III.  PART  II.  H 


114  lODOL. 

Two  isomeric  methyl-pyrrols  exist  in  bone-oil,^  resides  a  dimethijl- 
pyrrol,  boiling  at  165°,  which  has  also  been  obtained  synthetically, 
and  closely  resembles  pyrrol.  In  the  homologues  of  pyrrol  occurring 
in  bone-oil,  substitution  has  always  occurred  in  the  C^H^  group, 
but  by  the  action  of  alkyl  iodides  on  potassium-pyrrol  substitution 
of  the  hydrogen  of  the  NH  group  can  be  effected. 

Tetraiodo-pyrrol,  C^I^NH,  has  been  recently  introduced  into 
medicine  under  the  name  of  "  i  o  d  o  1."  It  is  prepared  by  the 
action  of  iodised  potassium  iodide  on  pyrrol,  and  forms  a  tasteless, 
pale  yellow,  crystalline  powder,  having  a  faint  thymol-like  odour. 
It  is  unchanged  at  100°,  but  gives  off  iodine  vapour  at  a  somewhat 
higher  temperature.  lodol  is  nearly  insoluble  in  water,  but  readily 
in  ether  and  chloroform.  It  dissolves  in  three  parts  of  alcohol,  and 
the  solution  is  precipitated  by  adding  water,  but  not  by  glycerin, 
lodol  contains  90  per  cent.  of.  iodine  and  possesses  antiseptic  and 
local  anaesthetic  properties  analogous  to  those  of  iodoform,  over 
which  its  slight  odour  and  freedom  from  toxic  properties  give  it 
the  preference.  lodol  can  be  recognised  by  the  green  colour  of 
its  solution  in  sulphuric  acid,  and  by  the  bright  red  colour  produced 
when  an  alcoholic  solution  is  warmed  with  nitric  acid. 


QUINOLINE  AND  ITS  ALLIES. 

The  interesting  base  which  gives  its  name  to  the  quinoline  series 
bears  the  same  relation  to  naphthalene  that  pyridine  bears  to  ben- 
zene ;  that  is,  it  is  derived  by  the  substitution  of  an  atom  of  nitro- 
gen for  one  of  the  CII  groups  of  naphthalene  (see  foot-note,  Yol. 
II.  page  507)  :— 

Pyridine,         .         .     C5H5N 


Benzene, .         .         .     CgHg 
Naphthalene,    .  .     CjoHg 


Quinoline,       ,         .     CgH^N 


■with  a  large  excess  of  solid  caustic  potash  in  a  reflux  apparatus  until  the 
whole  is  fused,  when  any  unchanged  oil  is  separated  and  the  crystalline 
mass  of  potassium  pyrrol,  C4H4KN,  is  powdered,  and  after  being  washed 
with  ether  is  treated  with  water  and  distilled  with  steam,  when  the  pyrrol 
is  regenerated. 

1  To  isolate  these  methyl-pyrrols,  the  fraction  of  bone-oil  boiling  between 
1.40°  and  150°  is  converted  into  the  potassium  derivative,  and  this  is  heated 
to  200°  in  a  stream  of  carbon  dioxide.  Two  isomeric  homopyrrol- 
carboxylic  acids  are  formed.  The  o-acid  melts  at  169°  "5,  and  forms  a 
lead  salt  very  soluble  in  water,  while  the  )8-acid  melts  at  142°'4,  and  forms  a 
nearly  insoluble  lead  salt.  On  distilling  the  respective  acids  with  lime,  the 
corresponding  o-  and  )8-homopyrrols  are  regenerated.  The  first  boils  at  148° 
and  the  latter  at  143°  at  743  mm.  pressure. 


QUINOLINE   SERIES. 


115 


QuinoHne  may  be  represented  by  the  following  constitutional 
formulae.  Where  substitution  occurs  in  the  pyridine-nucleus,  a,  ]8, 
and  7  (or  P-1,  -2,  and  -3)  products  are  obtained,  while  substitu- 
tion in  the  benzene-nucleus  yields  ortho-,  meta-,  para-,  and  ana- 
derivatives  (or  B-1,  -2,  -3,  -4),  according  to  the  position  of  the 
substituted  hydrogen  atom. 

CH     en 


Fig.  2. 


Fig.  3. 


Just  as  two  isomeric  naphthols  exist,  so  two  isomeric  quinolines 
are  theoretically  possible,  and  appear  to  have  been  obtained.  Thus 
the  quinoline  obtained  by  distilling  quinine,  cinchonine,  and  other 
alkaloids  with  potash  (fig.  2)  appears  to  dijQfer  in  some  of  its  re- 
actions from  the  quinoline  contained  in  coal-tar,  which  is  often 
called  1  e  u  c  o  1  i  n  e  (fig.  3).,  On  the  other  hand,  Hoogewerff 
and  Van  Dorp  {Jour.  Chem.  Soc,  xliv.  89)  contend  that  the 
quinolines  obtained  from  both  sources  are  identical. 

A  whole  series  of  higher  homologues  are  produced,  together  with, 
quinoline,  on  distilling  alkaloids  with  caustic  potash.^  y-methyl 
quinoline  or  lepidine,  C^q{CJ{^^,  the  first  member  of  the  series, 
boils  at  266°.  Of  the  next  member,  despoline,  CiiH^^N,  and  the 
still  higher  homologues,  very  little  is  known. 

A  parallel  series  of  bases  have  been  found  in  coal-tar  and  shale- 
oils.  They  are  obtained  from  the  fractions  of  the  bases  boiling 
above  200°,  and  hence  distil  after  the  pyridine  bases  have  passed 
over.  Quinaldine,  or  a-methyl-quinoline,  C9Hg(CH3)I^, 
boils  at  239°,  and  sometimes  forms  25  per  cent,  of  coal-tar  quino- 
line. It  is  a  colourless  liquid  (also  obtainable  synthetically),  the 
oxidation  of  which  yields  either  a  benzene  or  a  quinoline  derivative, 
according  to  the  nature  of  the  oxidising  agent.^  IridoUne,  isomeric 
with  quinaldine,  and  probably  identical  with  lepidine,  is  also  con- 

*  If  the  distillation  be  conducted  in  presence  of  copper  oxide,  the  quinoline 
obtained  is  almost  free  from  higher  homologues. 

^  When  quinaldine  is  heated  with  amyl  iodide  it  forms  the  compound 
CjH6(CH3)(C5Hji)NI,  which  on  heating  with  caustic  potash  is  converted  into 
a  cyan  in  e,  CggHsjNI  (page  118).  A  similar  body  is  obtainable  from  lepi- 
dine, and  a  mixture  of  the  two  has  been  used  for  dyeing  silk,  but  the  colour  is 
very  fugitive.  When  heated  with  phthalic  anhydride,  quinaldine  reacts  to 
form  a  body  of  the  phthalein  class  known  as  quinoline-yellow  (see  Vol,  III. 
Part  I.  page  174). 


116 


QUINOLINE   SERIES. 


tained  in  coal-tar.     It  boils  between  252°  and  257°,  and  yields 
a  crystallisable  nitrate,  chromate,  and  hydrochloride. 

From  the  acid  tar  produced  in  the  purification  of  shale-oil, 
Robinson  and  Goodwin  {Trans.  Roy.  Soc.  Edin.,  xxviii.  561; 
xxix.  265)  obtained  the  following  bases  of  the  quinoline  series. 


Base. 

Formula. 

Boiling-Point,  '  C. 

Tetracoline, 

C10H13N 

290-295 

Pentacoline, 

C13H15N 

305-310 

Hexacoline, .       ,       ,       . 

C14H17N 

325-330 

Heptacoline, 

C15H19X 

345-350 

Octacoline,  .... 

CigHoiN 

360-365 

Quinoline,     Chinoline.     CgH-N. 

This  base  is  formed  by  distilling  quinine,  cinchonine,  or  strych- 
nine with  aqueous  potash,  and  by  other  interesting  reactions ;  but 
is  best  prepared  by  shaking  together  nitrobenzene  (48  parts),  aniline 
(76  parts),  glycerin  (240  parts),  and  sulphuric  acid  (200  parts). 
"When  the  aniline  sulphate  has  dissolved,  a  reflux  condenser  is  fitted 
to  the  flask,  which  is  heated  to  130°  till  reaction  sets  in,  when  the 
flame  is  removed.  In  about  three  hours,  or  when  action  is  at  an 
end,  the  product  is  cautiously  diluted  with  water,  and  boiled  to 
get  rid  of  traces  of  nitrobenzene,  after  which  lime  or  caustic  soda 
is  added,  and  the  quinoline  and  unchanged  aniline  distilled  over  in  a 
current  of  steam.  The  oil  obtained  is  separated  from  the  aqueous 
layer,  dehydrated  over  caustic  potash,  and  fractionally  distilled, 
whereby  a  separation  of  the  bases  is  eff'ected  tolerably  readily, 
aniline  boiling  at  184°,  and  quinoline  at  239°.  To  purify  the 
latter  it  is  again  fractionally  distilled,  and  boiled  with  weak  chromic 
acid  mixture  (to  oxidise  any  aniline) ;  or  the  quinoline  is  dissolved 
in  six  parts  of  water,  and  strong  sulphuric  acid  added  in  the  exact 
quantity  necessary  to  combine  with  the  base.  After  cooling,  the 
liquid  is  filtered,  and  the  insoluble  acid  sulphate  washed  with 
alcohol  till  snow-white,  and  then  decomposed  by  potash.^    • 

^  The  reaction  in  the  foregoing  reaction  may  be  written  thus  : — 
2C6H^N  +  CgHgNOa  +  3C3H803  =  3C9H7N  +  NH,0 . 
The  change  is  undoubtedly  due  to  the  formation  of  a  c  r  o  1  e  i  n,  C3H4O,  from  the 
glycerin,  and  the  reaction  of  this  with  aniline  to  form  acrolein-aniline, 
with  simultaneous  oxidation  by  the  nitrobenzene  : — 

CsHgOa  +  CgHgNHg  +  0  =  C9H7N  +  4H2O . 
The  homologues  of  quinoline  may  be  obtained  in  an  analogous  manner,  and  by 


QUINOLINE.  n  7 

Quinoline  is  a  colourless  mobile  liquid,  having  a  penetrating  and 
peculiar  taste,  and  an  after-taste  slightly  resembling  peppermint- 
oil.  It  has  a  faint  aromatic  odour,  like  that  of  bitter-almond  oil. 
Quinoline  evaporates  completely  but  slowly  at  the  ordinary  tempera- 
ture, so  that  the  grease-spot  formed  by  it  on  paper  is  not  permanent. 
It  boils  at  238°-239°,  according  to  most  observers;  231°*5, 
according  toSpaleholtz;  and  241°*3,  according  to  Kretschy. 
Its  specific  gravity  is  stated  to  be  I'OSl  at  0°  C,  and  1*094  at 
20°  C.,  compared  with  water  at  the  same  temperature. 

Quinoline  is  very  sparingly  soluble  in  cold  water,  but  more  freely 
so  in  hot.  It  is  miscible  in  all  proportions  with  alcohol,  ether,  carbon 
disulphide,  and  fixed  and  volatile  oils ;  and  is  also  easily  soluble 
in  chloroform,  amylic  alcohol,  benzene  and  petroleum  spirit. 

On  exposure  to  air,  quinoline  becomes  resinified. 

Quinoline  has  well-marked  basic  characters,  and  forms  an  extensive 
series  of  salts,  most  of  which  are  crystallisable  and  deliquescent.  It 
precipitates  ferric  and  aluminium  solutions,  and  at  a  high  tem- 
perature decomposes  ammonium  salts. 

Quinoline  can  be  titrated  fairly  accurately  with  standard  acid,  it 
methyl-orange  be  employed' as  an  indicator. 

Reactions  of  Quinoline  and  its  Salts. 

Quinoline  salts  in  aqueous  solution  are  precipitated  milky  white- 
by  caustic  alkalies  and  ammonia,  the  precipitate  being  somewhat, 
soluble  in  excess.  From  the  alkaline  liquid,  the  quinoline  can  be- 
readily  extracted  by  ether,  chloroform,  or  petroleum  spirit. 

Iodised  iodide  of  potassium  gives  a  reddish-brown  precipitate 
even  in  dilute  solutions  of  quinoline  salts  (1  in  20,000).  Potassio- 
mercuric  iodide  only  precipitates  quinoline  from  tolerably  strong 
solutions  (1  in  3000),  the  precipitate  being  yellowish  white  and 
amorphous,  but  converted  into  delicate  amber-yellow  needles  on 
addition  of  hydrochloric  acid.  This  reaction  is  characteristic. 
Phosphomolybdic  acid,  in  presence  of  nitric  acid,  produces  a. 
yellowish-white  precipitate  in  quinoline  solutions. 

Potassium  ferrocyanide  colours  solutions  of  quinoline  salts  reddish,, 
and  on  addition  of  hydrochloric  acid  a  reddish-yellow  amorphous 
precipitate  is  thrown  down,  if  the  liquid  be  not  too  dilute. 

Quinoline  is  precipitated  by  picric  acid,  but  not  by  tannic  acid 
or  ferric  chloride;  and  its  salts,  in  the  solid  state,  yield  no  colour- 
reactions  with  nitric  acid  or  strong  sulphuric  acid,  either  alone  or  in 
association  with  oxidising  agents. 

With  potassium  bichromate,  if  carefully  added,  quinoline  salts 

em]iloying  derivatives  of  aniline  or  its  homologues,  quinoline  substituted  in 
the  benzene-ring  may  be  obtained. 


118  QUINOLINE. 

yield  a  precipitate  of  delicate  dendritic  crystals  of  the  bichro- 
mate (CQiij^)Ii^,Crfi^,  said  by  Donath  to  be  soluble  in  excess 
of  the  reagent.     Quinoline  bichromate  melts  at  165°  C. 

When  quinoline  is  heated  with  sodium,  diquinolyline, 
CgHgN.CgHgN,  analogous  to  dipyridyl  and  diphenyl,  is  formed. 
When  polymerised,  quinoline  yields  yellow  needles  of  diquino- 
line,  (C9H7N)2. 

When  quinoline  and  amyl  iodide  are  boiled  together  for  a 
short  time,  they  combine  to  form  a  crystalline  body  containing 
09X17(0511^1)^1.  If  the  product  be  dissolved  in  boiling  water, 
and  tlie  solution  filtered  and  boiled  with  caustic  soda  or  ammonia, 
avoiding  excess,  a  blue  colouring  matter  is  formed,  which,  on  allow- 
ing the  liquid  to  cool,  is  precipitated,  leaving  the  solution  nearly 
colourless.  The  separated  substance,  called  c  y  a  n  i  n  e,  is  a  basic 
body  crystallising  in  green  plates,  having  a  metallic  lustre.  It  is 
nearly  insoluble  in  cold  water,  but  dissolves  in  alcohol  to  form  a 
rich  purplish  blue  solution,  which  dyes  silk  blue. 

The  foregoing  reaction,  as  also  that  with  potassium  bichromate,  is 
said  not  to  be  obtainable  with  the  quinoline  (leucoline)  of  coal-tar. 

Quinoline  possesses  powerful  antiseptic  properties.  0'2  per  cent, 
of  the  tartrate  is  said  to  completely  prevent  the  lactic  fermentation 
of  milk,  the  decomposition  of  urine  and  gelatin,  and  the  develop- 
ment of  bacteria  in  cultivation-fluid.  Even  in  concentrated  solu- 
tion it  does  not  coagulate  albumin,  and  in  the  proportion  of  1  per 
cent,  it  completely  destroys  the  coagulability  of  the  blood.  On  the 
other  hand,  quinoline  is  remarkably  inactive  to  yeast-cells,  and 
does  not  atfect  the  alcoholic  fermentation,  even  when  present  in 
considerable  quantity. 

Quinoline  has  been  used  in  medicine  as  an  antipyretic,  the  adult 
dose  of  the  tartrate  being  from  7  to  1 2  grains.  It  is  said  by  some 
not  to  produce  any  unpleasant  after-effects,  but  by  others  to  cause 
irritation  of  the  stomach  and  collapse.  It  is  not  found  in  the  urine 
of  those  who  have  taken  it  internally. 

Commeixial  Quinoline  is  often  very  impure  and  quite  unfit  for 
medicinal  use.  0.  Ekin  (Pharm.  Jour.,  [3],  xii.  661)  has 
described  a  specimen  which  had  a  deep  brown  colour  and  an  odour 
like  oil  of  bitter  almonds.  On  treating  it  with  hydrochloric  acid 
a  large  proportion  remained  insoluble,  and  was  evidently  uncon- 
verted nitrobenzene,  while  the  soluble  part  gave  the  reactions  of 
aniline. 

Cinchonine-quinoline  often  contains  lejndine.  Such  samples 
give  the  cyanine  reaction  (see  above)  with  amyl  iodide  and  caustic 
alkali. 

The  salts  of  quinoline  should  be  completely  soluble  in  water, 


QUINOLINE   DERIVATIVES.  11& 

and  the  free  base  in  a  slight  excess  of  hydrocliloric  acid.  The 
neutral  solution  should  be  free  from  bitter  taste  (which  indicates 
the  presence  of  impurity  derived  from  cinch  onine),  and  should  not 
give  a  coloured  precipitate  with  caustic  alkalies. 

Quinoline  Tartrate^  {Qi^,j^\{C^^O^^,  is  now  used  extensively 
in  medicine.  It  melts  at  125°  C,  and  possesses  the  advantage  of 
being  permanent  in  the  air,  whereas  most  of  the  salts  of  quinoline 
are  deliquescent.  It  dissolves  in  80  jDarts  of  cold  water,  in  about 
150  parts  of  rectified  spirit,  and  in  350  parts  of  ether.  It  produces 
much  the  same  effects  as  sulphate  of  quinine,  and  is  given  in  similar 
doses,  but  is  far  lower  in  price. 

Quinoline  Hydrocldoride,  C9HyN,HC1,  melts  at  94°  C,  and  sub- 
limes unchanged.  It  dissolves  in  water,  alcohol,  and  chloroform, 
and  sparingly  in  cold  ether  and  benzene. 

Tetrahydroquinoline. 

e,H„N;orCA{CW| 

When  quinoline  is  acted  on  by  nascent  hydrogen,  it  is  first  con- 
verted into  dihydroquiiioline,  CqHqN,  a  solid  body  melting 
at  161°,  and  subsequently  into  tetrahydroquinoline,  which 
is  a  liquid  boiling  at  245°.  Both  these  reduction-products  yield 
nitrosamines,  and  can  be  alkylated,  and  hence  are  secondary  bases. 
Tetrahydroquinoline  possesses  stronger  antipyretic  characters  than 
quinoline  itself,  and  this  property  is  exhibited  still  more  strongly 
in  certain  of  its  derivatives,  several  of  which  have  received  some 
api^lication  in  medicine  (see  below). 

Antipyretics  allied  to  Quinoline. 

A  considerable  number  of  new  substances  related  to  quinoline, 
and  mostly  allied  to  tetrahydroquinoline,  have  been  recently  intro- 
duced as  febrifuges  and  antipyretics.  Some  of  these  are  very 
powerful  in  their  action,  and  ap})ear  likely  to  receive  a  permanent 
place  in  medicine ;  but  they  are  not  periodics,  and  cannot  be  sub- 
stituted for  quinine  in  cases  of  ague  or  intermittent  fevers.  The 
following  are  the  most  important  of  the  antipyretics  derived  from 
or  related  to  quinoline.^ 

il/-KAiROLiNE  is  the  acid  sulphate  of  a  base  having  the  constitu- 

^  Other  antipyretics  are  described  in  the  sections  on  anilides,  amidophenols, 
antipyrine,  &c.  Many  interesting  facts  relating  to  and  relationships  of  the 
antipyretics  have  been  collated  by  T.  S.  Dymond  and  an  anonymous 
German  author  {Pharm.  Jour.,  [3],  xvii.  886-895).  A  fuller  and  more  recent 
description  of  them  is  given  in  a  series  of  articles  on  "  Modern  Materia  Medica," 
contributed  by  H.  Helbing  to  the  British  arid  Colonial  Druggist,  1891,  and 
since  published  in  a  separate  form. 


120  KAIRINES. 

tion  of  methyl-tetrahydro-quinoline,  C9Hjq(CH)3N, 
obtained  by  reducing  quinoline  by  tin  and  hydrochloric  acid,  and 
reacting  on  the  resulting  tetrahydroquinoline  with  methyl  iodide. 

^-Kairoline  had  a  similar  constitution,  but  contained  ethyl, 
C2H5,  instead  of  the  methyl-group. 

ilf-KAiRiNE    is    the    hydrochloride     of     Hydroxy-tetra- 
hydro-methyl-quinoline, 
p  XT  /rkTT\    /  CHg.CHg.         ]  The  corresponding  ethyl-derivative 
^Q^zK^^)  '  I  N(CH3).CH2.  I  is  known  as  A-Kcdrine. 

On  adding  a  caustic  alkali  to  the  aqueous  solution  of  a  kairine, 
the  penetrating  characteristic  odour  and  bitter  taste  of  the  free  base 
are  easily  recognised,  while  the  alkaline  solution  rapidly  becomes 
coloured  and  deposits  a  brown  humus-like  substance.  When  the 
aqueous  or  alcoholic  solution  of  a  kairine  is  treated  with  an  oxidising 
agent,  such  as  potassium  bichromate  and  an  acid,  it  gives  a  series 
of  colours  ranging  from  violet-blue  to  purple,  or  sometimes  greenish. 
Without  the  addition  of  an  acid,  the  solution  becomes  dark  purple, 
and  on  standing  a  violet  precipitate  is  formed,  which  dissolves  in 
alcohol  with  black  colour.  A  drop  of  ferric  chloride,  added  to  a 
dilute  and  neutral  solution  of  kairine,  instantly  produces  a  violet 
coloration,  rapidly  changing  to  brown,  with  precipitation.  An 
excess  of  ferric  chloride  added  to  a  strong  solution  of  kairine  produces 
a  nearly  black  precipitate.  Sodium  nitrite  and  dilute  sulphuric 
acid  produce  an  orange  or  red  colour  in  kairine  solutions.  Potassium 
ferrocyanide  gives  a  voluminous  precipitate,  and  phosphotungstic 
acid  a  pale  yellow  precipitate. 

The  kairines  act  as  powerful  antipyretics.  Their  use  is  almost 
obsolete,  as  their  action  is  somewhat  uncertain ;  and  they  are  said 
to  be  liable  to  produce  vomiting,  cyanosis,  and  collapse. 

Thalline  is  the  commercial  name  of  another  antipyretic,  meta- 
meric  with  m-kairine,  and  having  the  constitution  of  a  salt  of 
tetrahydro-paraquinanisol : — 


CA(0.CH3):{CW| 


Thalline  is  prepared  by  heating  paramido-anisol  and  paranitro- 
anisol  with  glycerin  and  sulphuric  acid,  and  reducing  the  product 
with  nascent  hydrogen.  Thalline  base  crystallises  in  large  colour- 
less prisms,  having  a  bitter,  saline,  and  pungent  taste.  It  melts 
at  42°  C,  and  is  sparingly  soluble  in  water,  but  readily  in  alcohol, 
ether,  chloroform,  or  benzene. 

Thalline  Sulphate,  (CioHi3NO)2H2S04-|-2H20,  is  the  most  com- 
mon variety  of  commercial  "  thalline."  It  occurs  as  a  yellowish- 
white,  granular  or  crystalline  powder,  having  a  bitter,  aromatic  taste. 


THALLINE.  121 

and  a  faint  odour  resembling  anise  and  meadow-sweet.  It  dissolves 
in  seven  parts  of  cold  water,  but  only  sparingly  in  alcohol,  and  the 
solutions  become  darker  on  exposure  to  light.  A  very  dilute 
aqueous  solution  of  commercial  thalline  gives  with  ferric  chloride 
a  yellow  coloration,  changing  to  emerald-green  (destroyed  by 
reducing  agents),  and  passing  in  a  few  hours  to  deep  red.  The 
reaction  is  extremely  delicate.  A  green  colour  is  also  produced  by 
auric  chloride,  argentic  nitrate,  mercuric  nitrate,  chlorine-water, 
&c.,  and,  in  acid  solution,  also  by  solution  of  bleaching  powder  and 
potassium  ferricyanide.  Strong  sulphuric  acid  dissolves  thalline 
sulphate  without  coloration,  but  on  addition  of  nitric  acid  the  liquid 
becomes  deep  red,  and  immediately  afterwards  yellow-red.  Fuming 
nitric  acid  colours  a  dilute  aqueous  solution  reddish.  Sulphuric 
acid  and  sugar  give  a  red  coloration.  Iodine  colours  the  solution 
dark  brown,  then  dingy  green.  Ammonia  forms  a  white  precipitate 
of  the  free  base,  readily  taken  up  by  ether  on  agitation.  If  not 
too  dilute,  solutions  of  thalline  sulphate  yield  precipitates  with  the 
general  reagents  for  alkaloids. 

If  to  an  aqueous  solution  of  /3-naphthaquinone  a  small  quantity 
of  the  solution  of  a  thalline  salt  be  added,  and  then  a  drop  or  two 
of  caustic  soda  solution,  a  fine  cherry-red  coloration  is  produced, 
becoming  more  brilliant  on  adding  nitric  acid.  The  colouring  matter 
is  extracted  by  ether  or  chloroform. 

Thalline  Tartrate  occurs  in  commerce  as  a  yellow- white  crystal- 
line powder.  It  dissolves  in  ten  parts  of  cold  water,  and  the 
solution  gives  the  same  reactions  as  the  sulphate.  In  alcohol  it  is 
very  sparingly  soluble.    The  salt  contains  52*2  per  cent,  of  thalline. 

The  salts  of  thalline  become  altered  by  exposure  to  light. 

Thalline  salts  are  powerfully  antipyretic,  and  have  been  em- 
ployed in  yellow  fever.  They  cause  profuse  perspiration,  and  are  apt 
to  produce  depression,  &c.  Hence  their  internal  use  is  practically 
obsolete.  Thalline  acts  as  a  direct  blood-poison,  its  antithermic 
properties  being  due  to  the  destruction  of  the  red  corpuscles.  It 
has  found  considerable  application  in  the  treatment  of  gonorrhoea. 
The  sulphate  is  official  in  the  German  Pliarmaccypoeia  of  1890. 

Exhibition  of  thalline  causes  a  dark  coloration  of  the  urine.  A 
derivative,  which  also  gives  a  green  colour  with  ferric  chloride,  but 
differs  from  thalline  in  being  extracted  by  agitating  the  acidulated 
urine  with  petroleum  spirit,  should  first  be  removed,  and  then  the  un- 
altered portion  of  the  thalline  can  be  isolated  by  rendering  the  urine 
alkaline  with  ammonia,  and  agitating  with  ether  or  benzene.  Very 
small  quantities  of  thalline  can  in  this  way  be  recognised  in  urine. 

Ethyl-thalline,  CioIIioON(C2H5),  is  produced  by  heating  ordi- 
nary thalline  with  ethyl  iodide. 


122 


QUINAZOLINES. 


Thermifugin  is  a  name  given  to  the  sodium  salt  of  methyl- 
trihydroquinoline-carboxylic   acid :  — 

(COOKa)CA:{SfdHjcHj 
Quinazolines. 

By  the  replacement  of  one  of  the  CH  groups  of  quinoline  by  N, 
bodies  are  obtained  which  bear  the  same  relationship  to  quinoline 
that  the  azines  bear  to  pyridine.     Thus  : — 


Ortho-azine 
(Oiazine). 

^{:cH."cH>H 

Meta-azine 
(^Miaziue). 


Quinoline. 

„f:CH.CH.- 


CH 


Ortho-guinazoline 
(Pheuoiazine). 


CH 


Para-azine 
(Piazine). 

:CH.CH: 
.CH:CH. 


|:CH.CH:| 
^  \  .CH:CH.  I  ^^ 


l-CeH,.    I 

Meta-quinazoliru 
(Pheumiazine) . 

Para-quinazolin 
(Phenpiazine). 


CH 


A  substituted  meta-quinazoline   having   the   constitution   of    a 
phenyl-dihydrophenmiazine : — 


^f:CH.N(C,H,).| 


has  recently  acquired  some  practical  interest  as  the  base  of  "o  r  e  x  i  n," 
a  preparation  said  to  have  valuable  tonic,  stomachic,  and  appetising 
properties,  on  which,  however,  some  doubt  has  been  thrown  {Pharm. 
Jour.,  [3],  XX.  709,  825,  977  ;  xxi.  43).  The  usual  dose  of  orexin 
is  from  2  to  10  grains. 

Orexin,  which  occurs  as  a  hydrochloride  having  the  composition 
Ci4nj2N2,HCl+2H20,  is  prepared  by  reacting  on  the  sodium- 
derivative  of  formanilide  by  ortho-nitrobenzyl  chloride,  according 
to  the  equation: — 

Na(CHO).N.C6H5  +  Cl.CH2.C6H4.N02-NaCl  +  CHO.N(C6H5).CH2.C6H4.N02 

The  nitrobenzyl-formanilide,  on  reduction  with  tin  and  hydro- 
chloric acid,  forms  the  closed  chain  compound  which  is  the  base  of 
orexin : — 


OREXIN.  123 

Orexin  (hydrochloride)  crystallises  with  2H2O  in  white  needles, 
melting  at  80°.  When  kept  under  an  exsiccator  for  some  time 
they  become  anhydrous,  and  then  melt  at  221°.  Orexin  has  a 
bitter  taste,  and  somewhat  intense,  burning  after-taste.  The  powder 
induces  violent  sneezing.  Orexin  dissolves  readily  in  water  (13 
parts)  and  alcohol,  but  not  in  ether.  On  adding  an  alkali  to  the 
aqueous  solution  the  free  base  is  separated  as  a  white  flocculent  pre- 
cipitate readily  soluble  in  ether  and  chloroform.^  A  solution  of 
orexin  yields  with  mercuric  chloride  a  white  precipitate  soluble  in 
hot  water,  and  redeposited  in  white  needles  on  cooling.  Potassium 
bichromate  gives  a  yellow  precipitate  soluble  on  heating,  and 
redeposited  on  cooling  in  golden  yellow  needles.  Bromine-water  is 
decolorised  with  formation  of  a  yellowish  amorphous  precipitate. 
Orexin  reduces  potassium  permanganate  in  the  cold. 

On  heating  orexin  in  a  test-tube  with  about  twice  its  measure 
of  zinc-dust,  the  strong  characteristic  odour  of  phenyl-isonitrile  is 
produced.  On  treating  the  residue  with  hydrochloric  acid,  and 
adding  bleaching-powder  solution  to  the  filtered  liquid,  a  blue 
coloration  is  obtained,  owing  to  the  previous  formation  of  aniline 
(compare  page  45). 


ACRIDINE  AND  ITS  ALLIES. 

Acridine  and  its  isomer  phenanthridine  bear  the  same 
relation  to  anthracene  and  phenanthrene  respectively  that  quinoline 
bears  to  naphthalene,  and  pyridine  to  benzene  (compare  page  39). 
The  following  formulae  show  their  constitution  and  relationship  to 
anthracene  and  phenanthrene : — 

CeH,:|?|:C.H,  { WHjl} 

Anthracene.  Phenanthrene. 

CeH.:|?}:CA  ^^'^  }] 

Acridine.  Phenanthridine. 

Acridine.    C13H9N 

Acridine  has  been  prepared  synthetically  by  heating  concentrated 
^  The  base  sometimes  separates  as  an  oil,  which  afterwards  crystallises. 


124  ACRIDINE. 

formic  acid  or  chloroform  with  diphenylamine  and  zinc  chloride/ 
and  also  by  various  other  reactions.  Acridine  is  contained  in 
coal-tar,  and  may  be  extracted  from  the  fraction  boiling  between 
300°  and  360°,  or  from  crude  commercial  anthracene,  by  agitating 
it  with  dilute  sulphuric  acid,  precipitating  the  acid  liquid  with 
potassium  chromate,  purifying  the  acridine  chromate  by  recrystal- 
Hsation,  precipitating  the  base  by  ammonia,  and  recrystallising  it 
from  hot  water.  The  hydrochloride  may  also  be  employed  for  the 
purification  of  acridine. 

Acridine  forms  colourless  or  brownish-yellow  rhombic  prisms,  of 
very  pungent  odour  and  burning  taste.  It  melts  at  107°,  sublimes 
in  broad  needles  at  about  the  same  temperature,  boils  unchanged 
at  360°,  and  distils  with  the  vapour  of  water. 

Acridine  is  very  slightly  soluble  in  cold,  but  more  readily  in 
boiling  water,  crystallising  on  cooling  in  long  needles.  It  is  readily 
soluble  in  alcohol,  ether,  benzene,  carbon  disulphide,  &c. 

Dilute  solutions  of  acridine  (and  its  salts)  exhibit  a  strong  blue 
fluorescence,  which  is  green  in  more  concentrated  solutions,  and 
disappears  if  they  are  very  strong. 

Certain  reactions  of  acridine  solutions  with  reagents  are  described 
on  page  126. 

The  most  characteristic  property  of  acridine  is  its  intensely 
irritating  effect  on  the  skin  and  mucous  membrane.  Violent  sneezing 
and  coughing  are  produced  by  inhaling  the  smallest  particle  of  the 
dust  or  vapour.  The  base  and  its  salts  attack  the  tongue  even  in 
minute  quantities,  and  even  very  dilute  solutions  cause  acute  sting- 
ing when  applied  to  the  tongue  or  skin. 

Acridine  has  been  employed  as  an  insecticide,  and  compositions 
containing  it  have  been  patented  for  coating  the  bottoms  of  vessels. 
It  is  highly  probable  that  the  preservative  properties  of  coal-tar 
creosote  oil  are  partially  due  to  the  presence  of  acridine. 

Acridine  is  a  very  stable  substance.  Sulphuric  acid  has  no 
action  upon  it,  except  at  a  very  high  temperature,  and  caustic 
potash  does  not  react  below  280°.  Concentrated  nitric  acid  con- 
verts acridine  into  nitro-derivatives.  Most  other  oxidising 
agents  act  with  difficulty  or  not  at  all  on  acridine,  but  by  the  action 

^  Acridine  is  best  obtained  by  heating  a  mixture  of  one  part  each  of  chloro- 
form, diphenylamine,  and  zinc  or  (preferably)  aluminium  chloride,  with  one-half 
part  of  zinc  oxide,  for  seven  or  eight  hours,  under  pressure,  to  200°-210''  C. 
The  product  is  boiled  with  concentrated  hydrochloric  acid,  the  filtered  liquid 
poured  into  water,  the  liquid  again  filtered,  the  acridine  precipitated  from 
the  solution  by  ammonia,  and  recrystallised  from  hot  water  (Fischer  and 
K  0  r  n  e  r,  Ber.^  xvii.  101).     The  reaction  is  as  follows ; — 

(C6H5)2NH  +  CHCl3  +  ZuO-C,3H,N,HCl  +  ZnC]2  +  H20. 


SALTS   OF   ACRIDINE.  125 

of  potassium  permanganate  it  has  been  converted  into  quinoline- 
dicarboxylic   or  acridinic   acid. 

Acridine  is  a  tertiary  amine.     It  unites  with  methyl  iodide. 

Salts  of  Acridine. 

Acridine  is  a  feeble  base.  It  forms  no  carbonate,  and  its  salts 
are  more  or  less  decomposed  by  boiling  with  a  large  quantity  of 
water. 

Acridine  HydroMoride,  CigHgNjHCl,  forms  yellow  plates. 
The  solution  in  water  exhibits  a  bluish-green  fluorescence,  and 
gives  a  yellow  crystalline  precipitate  of  the  mercwo-chloride, 
(Ci3H9N,HCl)2HgCl2,  on  adding  mercuric  chloride.  With  platinic 
chloride  it  yields  the  cJiIoroplatinate,  (Ci3HgN)2H2PtClg,  in  minute, 
sparingly  soluble,  yellow  needles. 

Acridine  Nitrite,  (Ci3H9N)2,HN02,H20-i-2  aqua,  is  obtained  as 
a  yellow  flocculent  precipitate  on  mixing  solutions  of  acridine  hydro- 
chloride and  sodium  nitrite.  It  forms  long,  yellow,  silky  needles, 
melting  at  151°,  somewhat  volatile  with  steam,  slightly  soluble  in 
ether  or  cold  water,  more  readily  in  hot  water,  and  very  soluble  in 
alcohol. 

Acridine  Sulphite,  (Ci3HgN)2,H2S03,  is  precipitated  in  yellowish- 
red  or  brDwnish  needles,  very  slightly  soluble  in  water,  on  mixing 
solutions  of  sodium  sulphite  and  acridine  hydrochloride,  and  adding 
hydrochloric  acid.^ 

Acridine  Picrate,  C;^3ngiS',CgH3(N02)3.  This  compound  is  ob- 
tained as  a  canary-yellow  precipitate,  consisting  of  minute,  yellow, 
prismatic  needles,  which  melt  with  blackening  at  208°.  It  is 
almost  wholly  insoluble  in  cold,  and  is  partially  decomposed  by 
boiling  water ;  it  is  but  slightly  dissolved  by  alcohol  or  benzene 
even  when  boiling.  Acridine  has  been  suggested  by  Anschiitz 
{Ber.,  xvii.  438  ;  Jour.  Soc.  CJiem.  Ind.,  iii.  234)  as  a  suitable 
reagent  for  the  determination  of  picric  acid,  the  hydrochloride  being 
used  as  a  precipitant  for  metallic  picrates,  and  a  solution  of  the  free 
base  in,  benzene  for  the  picric  acid  compounds  of  hydrocarbons. 

HtDROACEIDINE.      DiHYDRO acridine.       CgH^  \    Nvt  (  ^6^4" 

This  substance  is  formed  (together  with  a  white  substance  in- 
soluble in  alcohol)  by  the  reduction  of  acridine  in  alcoholic  solution 
by  sodium-amalgam.  It  forms  prisms  melting  at  169°,  insoluble 
in  water,  slightly  soluble  in  cold  alcohol,  very  soluble  in  hot  alcohol 
or  ether.  It  dissolves  in  concentrated  sulphuric  acid,  and  is  pre- 
cipitated unchanged  on  dilution  with  water.     Argentic  and  cupric 

^  Before  adding  acid,  the  liquid  contains  the  compound  C13H9N  NaHSOs, 
which  forms  colourless  easily  soluble  prisms. 


126  PHENANTHRIDINE. 

oxides  reconvert  it  into  acridine.     Hydroacridine  is  the  analogue 
of  piperidine  (page  106)  and  tetrahydroquinoline  (page  119). 


f  C,H,.CH:  )] 
tCeH,.N:     |f 


PhEN  ANTHRIDI NB. 

'    'V 

Phenanthridine  is  isomeric  with  acridine,  bearing  the  same 
relation  to  phenanthrene  that  acridine  bears  to  anthracene  (P  i  c  t  e  t 
and  Ankersrait,  Ber.,  xxii.  3339  ;  Jo7ir.  Soc.  Chem.  Ind.,  ix. 
280).  It  melts  at  104°  and  boils  about  360°.  Phenanthridine 
presents  the  closest  resemblance  to  acridine,  the  chief  difference 
being  in  its  behaviour  with  reducing  agents,  for,  while  acridine 
yields  on  reduction  a  non-basic  derivative,  phenanthridine  gives  a 
hydro-base,  which  crystallises  from  alcohol  in  white  needles 
melting  at  100°,  and  is  converted  by  nitrous  acid  into  a  nitros- 
amine.  The  mercuro-chloride  of  acridine  melts  at  225°;  the 
corresponding  compound  of  phenanthridine  at  190°.  On  adding 
sodium  sulphite  to  a  solution  of  the  hydrochloride  of  acridine,  a  pre- 
cipitate of  reddish-brown  needles  is  produced,  while  phenanthridine 
yields  no  precipitate. 


VEGETABLE  ALKALOIDS, 


The  term  "  alkaloid  "  was  originally  applied  to  the  various  basic 
principles  existing  naturally  in  plants.  As  the  number  of  known 
animal  bases  increased  in  number,  it  became  necessary  to  describe 
the  plant-bases  as  "  vegetable  alkaloids  "  to  distinguish  them  from 
the  alkaloids  of  animal  origin.  But  with  the  advance  of  synthetical 
chemistry,  and  the  study  of  coal-tar  products,  an  enormous  number 
of  new  bases  were  prepared,  and  the  restriction  of  the  term  alka- 
loid to  the  natural  plant-bases  became  still  more  difficult.  Dis- 
coveries in  recent  years  have  clearly  established  the  fact  that  many 
of  the  plant-bases  are  related  to  pyridine  or  quinoline,  and 
several  of  the  alkaloids  have  been  obtained  by  actual  synthesis  from 
pyridine  or  its  derivatives.  In  other  cases,  such  as  cinchonine 
and  strychnine,  the  actual  synthesis  of  the  alkaloid  has  not  hitherto 
been  effected,  but  the  relationship  of  the  bases  to  pyridine  and 
quinoline  is  not  less  certain.  On  the  other  hand,  some  of  the 
plant-bases  stand  in  much  closer  relation  to  uric  acid  and  the  bases 
found  in  the  animal  organism  than  they  do  to  the  other  plant- 
bases.  Thus  caffeine  and  theobromine  are  undoubtedly  uric  acid 
derivatives,  while  quinine  and  morphine  show  no  relation  to  uric 
acid,  being  evidently  pyridine  derivatives. 

K  0  n  i  g  s  has  proposed  to  restrict  the  term  "  alkaloid  "  to  bases 
belonging  to  the  second  of  these  classes,  and  to  define  alkaloids  as 
"  those  organic  bases  found  in  the  plant  kingdom  which  are  pyridine 
derivatives,"  and  it  seems  probable  that  this  proposal  will  gradually 
be  adopted,  at  least  in  effect. 

With  the  exception  of  a  limited  number  of  volatile  alkaloids 
{e.g.,  nicotine,  conine,  sparteine),  the  plant-bases  contain  oxygen 
in  addition  to  carbon,  hydrogen,  and  nitrogen.  They  are  analogues 
of  ammonia,  not  ammonium  bases  ;  that  is,  they  combine  with 
hydrochloric  acid  and  other  acids  without  elimination  of 
water. 

The  names  of  the  alkaloids  are  now  usually  made  to  terminate 
in  ine,  and  it  is  very  desirable  that  this  termination  should  be 


128  CHARACTERS    Oi    ALKALOIDS. 

strictly  confined  to  bodies  of  a  basic  nature.^  The  termination  ia 
is  still  employed  for  a  few  of  the  vegetable  alkaloids  (e.g.,  morphia), 
and  by  some  American  writers  for  certain  other  alkaloids.  The 
class  of  bodies  known  as  g  1  u  c  o  s  i  d  e  s — some  of  which  are 
described  in  an  appendix  to  this  chapter,  as,  from  an  analytical 
point  of  view,  they  present  some  similarity  to  the  alkaloids — 
should  receive  names  having  the  termination  in. 

The  true  vegetable  alkaloids  or  plant-bases  are  very  numerous. 
Many  of  them  are  but  imperfectly  known,  while  others  (e.g., 
morphine,  quinine,  strychnine)  have  been  studied  very  completely. 

The  alkaloids  as  a  class  are  found  in  all  parts  of  plants,  though 
in  some  cases  the  occurrence  of  particular  alkaloids  is  curiously 
restricted  to  certain  portions  of  the  plant.  Similarly,  many  of  the 
alkaloids  have  been  met  with  only  in  plants  of  a  particular  genus 
or  family,  and  in  some  cases  appear  to  be  characteristic  of  a  single 
species.2 

The  vegetable  alkaloids  are  in  many  cases  intensely  poisonous 
{e.g.,  aconitine,  veratrine,  strychnine),  while  others,  as  the  alkaloids 
of  coffee,  cocoa,  and  cinchona  bark,  produce  characteristic  physio- 
logical effects.     The  large  majority  of  them  have  a  bitter  taste. 

With  the  exception  of  the  non-oxygenated  volatile  bases,  nearly 

^  The  misuse  by  chemists  of  the  termination  ine  has  caused  great  confusion, 
which  its  employment  to  designate  indefinite  commercial  products  has  increased. 
There  is  no  excuse  for  writing  htuzire,  paraffme,  naphthaline  or  gelatme ; 
and  glycerine  is  also  an  undesirable  title.  The  recommendations  on  nomen- 
clature made  by  the  Publication  Committee  of  the  Journal  of  the  Chemical 
Society  deserve  more  attention  than  they  have  hitherto  received. 

2  J.  M.  M  a  i  s  c  h  {Pharm.  Jour.  [3],  xxi.  982 ;  from  Amer.  Jour.  Pharmacy) 
states  that  "  among  the  acotyledons  it  is  almost  exclusively  the  class  of  fungi 
which  in  its  different  groups  produces  alkaloids,  quite  distinct,  as  a  rule,  in  com- 
position and  effect,  from  those  generated  within  the  living  tissue  of  phanerogams. 
Such  alkaloids  are  in  nearly  all  cases  confined  to  a  single  species,  genus  or  tribe, 
and  only  in  rare  instances  have  been  met  with  in  several  orders.  Thus 
berberine  exists  in  plants  of  the  Ranunculacece,  Anonacece,  Menispermacece, 
Berberidacece,  Eutacece,  and  Leguminosece ;  and  caffeine  in  the  orders  of 
Eubiacece  (cofiee),  Ternstromiacece  (tea),  Sapindacece  (guarana),  Sterculiaeece 
(colo  and  cacao),  and  in  Ilidnece  (mate,  &c.).  But  colchicine  has  only 
been  observed  in  colchicum  ;  veratrine  and  j  e r v i n e  in  veratrum  ; 
piperine  in  certain  peppers  ;  quinine  and  allied  alkaloids  in 
cinchona  and  remijia  ;  strychnine  and  b  r  u  c  i  n  e  in  strychnos ;  mor- 
phine and  congeners  in  opium,  and  one  or  two  of  these  compounds  also  in 
other  poppies;  sanguinarine  in  a  few  Papaveracece ;  pilocarpine, 
physostigmine,  and  cocaine  (?),  each  only  in  a  single  species; 
aconitine  and  near  relatives  in  several  aconites ;  n  i c o  t i n e  in  species  of 
tobacco,  &c. "  The  mydriatic  alkaloids  of  the  Solaruiceoe  are  widely 
distributed  throughout  the  order. 


CHARACTERS   OF  ALKALOIDS.  129 

all  the  vegetable  alkaloids  are  solid  at  the  ordinary  temperature. 
They  are  in  most  cases  practically  fixed,  though  caffeine  and  a  few 
others  may  be  sublimed. 

Many  of  the  vegetable  alkaloids  are  powerfully  alkaline  in 
reaction,  neutralise  acids  perfectly,  and  form  well-defined  and 
crystallisable  salts.  In  other  cases  the  basic  character  is  only 
feebly  marked,  no  acetates  existing,  and  even  the  compounds 
with  the  stronger  acids  being  decomposed  by  mere  dilution  with 
water. 

Except  the  volatile  bases,  the  vegetable  alkaloids  are,  with  few 
exceptions  {e.g.y  curarine,  colchicine),  very  sparingly  soluble  in 
water,  and  are  consequently  precipitated,  more  or  less  perfectly,  on 
adding  caustic  potash  or  soda  to  the  solutions  of  their  salts.  In 
some  cases  the  precipitated  alkaloid  is  soluble  in  excess  of  the 
precipitant.  The  plant-bases  are  nearly  all  dissolved  by  alcohol 
(except  rhoeadine  and  pseudoraorphine),  and,  as  a  rule,  with  great 
facility.  The  salts  of  the  alkaloids  are  usually  more  soluble  in 
water  than  the  bases  themselves,  and,  as  a  rule,  dissolve  also  in 
alcohol.  This  is  true  of  the  sulphates  and  other  classes  of  alka- 
loidal  salts,  the  metallic  analogues  of  which  are  not  soluble  in 
alcohol. 

Certain  classes  of  double  salts  of  the  alkaloids  (e.g.,  chloro- 
platinates,  mercuro-iodides)  are,  as  a  rule,  very  insoluble  in 
water  (compare  pages  138,  143). 

Solvents  immiscible  with  water  differ  considerably  in  their 
action  on  alkaloids.  The  free  bases  are  for  the  most  part  soluble, 
especially  in  chloroform  and  amylic  alcohol,  but  in  the  great 
majority  of  cases  the  alkaloidal  salts  are  insoluble  in  such  menstrua. 
As,  however,  the  salts  of  the  alkaloids  of  low  basic  character  are 
decomposed  by  excess  of  water,  the  solutions  of  these  salts  often 
behave  with  immiscible  solvents  in  the  same  manner  as  the  free 
bases  (compare  pages  158,  159). 

Classification  of  Alkaloids. 

The  plant-bases  are  conveniently  studied  in  groups,  as  it  is 
found  that  the  alkaloids  of  a  certain  order  or  family  of  plants 
present  more  or  less  general  resemblance  in  properties  and  com- 
position. Thus  the  various  alkaloids  of  cinchona  bark,  of  opium, 
of  the  aconites,  &c.,  present  close  analogies  among  themselves. 
Other  alkaloids  do  not  readily  admit  of  being  thus  grouped, 
and  when  of  sufficient  importance  wiU  be  described  in  separate 
sections. 

In  describing  the  plant-bases  the  following  general  arrangement 
will  be  adopted  : — The  general  reactions  and  methods  of  extracting 
and  purifying  alkaloids  as  a  class  will  first  be   considered,  after 

VOL,  III.  PART  n.  I 


130  TITRATION   OF  ALKALOIDS. 

which  the  existing  knowledge  of  their  constitution  will  be  dis- 
cussed. The  non-oxygenated  volatile  bases  will  then  be  described. 
Then  will  follow  sections  on  the  more  important  saponifiable 
alkaloids,  such  as  the  aconite  and  mydriatic  alkaloids,  and  the 
bases  of  coca.  The  opium  bases  will  be  next  considered,  and  then 
strychnine  and  its  allies.  The  cinchona  bases  will  be  treated  in 
the  next  section,  which  will  be  followed  by  one  on  catFeine  and  its 
allies.  Such  of  the  alkaloids  as  have  not  been  described  under 
any  of  the  foregoing  classes,  and  which  are  of  sufficient  importance, 
will  then  be  described.  In  an  appendix  to  the  chapter  some  of  the 
more  important  vegetable  bitter  principles  of  non-basic  character 
will  be  shortly  described. 


GENERAL  REACTIONS  OF  ALKALOIDS. 

The  plant-bases  present  more  or  less  general  resemblance  in 
their  behaviour  with  certain  reagents,  and  hence  their  general 
reactions  are  classified  in  the  following  sections. 

Reactions  of  the  Alkaloids  with  Acids. 

As  bodies  of  basic  character,  the  alkaloids  combine  with  acids  to 
form  salts,  which  in  many  cases  are  crystallisable  and  more  or  less 
characteristic.  They  are  mostly  soluble  in  water  and  alcohol  (in- 
cluding the  sulphates),  but  insoluble  in  chloroform,  ether,  &c. 
Certain  of  the  salts  of  the  alkaloids  are  sufficiently  insoluble  to 
allow  of  the  precipitation  of  the  bases  for  purposes  of  determina- 
tion. Instances  of  this  occur  with  the  picrate  (berberine,  cincho- 
nine,  quinine),  acid  tartrate  (cinchonidine),  hydriodide  (quinidine), 
chromate  (strychnine),  hydroferrocyanide  (strychnine),  periodide 
(quinine,  atropine),  chloroplatinate  (berberine),  aurochloride 
{aconitine),  and  mercuro-iodide  (strychnine,  emetine,  colchicine). 

Titration  op  Alkaloids. — In  their  behaviour  with  indicators 
of  neutrality,  the  alkaloids  present  some  remarkable  dilBferences  of 
behaviour  from  inorganic  bases.  The  neutral  salts  of  strychnine, 
quinine,  morphine,  codeine,  conine,  nicotine,  and  other  strongly 
basic  alkaloids,  are  without  action  on  litmus,  and  these  alka- 
loids can  be  titrated  with  standard  acid  and  litmus,  just  like 
the  inorganic  bases,  except  that  their  high  combining  weights 
intensify  the  effect  of  the  errors  of  manipulation.  Some  of  the 
feebler  alkaloids,  including  narceine,  narcotine,  and  papaverine, 
have  no  action  on  litmus,  their  salts  behaving  exactly  like  a 
corresponding  amount  of  free  acid. 

The   salts   of   the  alkaloids  with  mineral  acids   are   generally 


TITRATION   OP  ALKALOIDS.  131 

neutral  to  methyl-orange,  which  indicator  can  therefore  be  used 
to  detect  and  determine  any  free  acid  present.'^ 

On  phenolphthdlein  the  great  majority  of  the  alkaloids  have 
no  action.  Hence,  after  neutralising  any  free  acid  with  the  help 
of  methyl-orange,  the  acid  in  combination  with  the  alkaloid 
present  can  in  most  cases  be  ascertained  by  titration  with 
standard  alkali  and  phenolphthalein,  and  where  the  combining 
weight  of  the  alkaloid  is  known  its  amount  can  be  calculated 
from  the  result  of  the  same  titration.  The  alkaloids  to  which 
the  process  is  not  applicable  are,  so  far  as  at  present  known, 
atropine,  homatropine,  hyoscyamine,  hyoscine, 
and,  according  to  P 1  u  g  g  e  {Arch.  Pharm.,  [3],  xxv.  45),  the  volatile 
alkaloids  c o n i n e  and  nicotine.  In  the  cases  of  brucine, 
morphine  and  thebaine,  a  red  coloration  is  obtained  somewhat 
before  the  end  of  the  reaction,  but  a  little  experience  is  stated  to 
surmount  this  difficulty.  M  o,r  p  h  i  n  e  acts  as  an  acid  to  Poirriers 
soluble  blue  (CLB),  probably  owing  to  the  presence  of  the  two 
hydroxyl  groups  (M.  K.  En  gel,  Compt  Bend.,  cii.  214). 

Lacmdid  has  been  used  by  Van  Itallie  {Analyst,  xiv.  118) 
for  the  titration  of  certain  alkaloids,  including  atropine,  hyoscy- 
amine and  Conine,  the  hydrochlorides  of  which  are  stated  to  be 
neutral  to  this  indicator. 

Rosolic  acid  has  been  employed  by  E.  Dieterich  (Pharm. 
Jour.,  [3],  xvii.  888)  for  the  determination  of  the  alkaloids  in 
extracts  of  aconite,  belladonna,  hyoscyamus,  conium,  and  nux 
vomica,  but  his  results  leave  the  value  of  the  indicator  somewhat 
in  doubt. 

Many  of  the  alkaloids  are  more  or  less  changed  when  heated 

^  In  titrating  an  alkaloid  with  methyl-orange,  it  is  rarely  convenient  to 
employ  an  aqueous  solution  of  the  base.  A  solution  of  the  alkaloid  in  proof 
or  rectified  spirit  is  generally  suitable,  and  the  indicator  is  fairly  sensitive 
under  such  conditions.  But  when  the  alkaloid  is  much  coloured,  as  is  fre- 
quently the  case  in  the  assay  of  the  bases  directly  extracted  from  their  sources, 
it  becomes  difficult  or  impossible  to  observe  the  end  of  the  reaction.  Under 
such  circumstances,  the  writer  has  overcome  the  difficulty  by  dissolving  the 
alkaloid  in  a  little  ether,  and  placing  the  solution  in  a  small  stoppered 
cylinder,  together  with  a  few  centimetres  of  water,  coloured  with  a  drop  of 
methyl-orange  solution  (1:1000).  On  then  gradually  dropping  in  the  standard 
acid  and  agitating  thoroughly  after  each  addition,  it  is  easy  to  observe  the 
end  of  the  reaction,  as  the  colouring-matter  remains  in  the  upper  ethereal 
stratum,  and  presents  a  marked  contrast  to  the  red  colour  of  the  aqueous 
liquid.  By  operating  in  this  manner  and  employing  ^  hydrochloric  acid,  the 
author  has  obtained  perfectly  satisfactory  estimations  of  aconitine,  &c.,  even 
when  working  on  as  little  as  0  '030  gramme. 


132  SAPONIFICATION  OF  ALKALOIDS. 

with  dilute  acids,  in  many  cases  suffering  hydrolysis  {e.g.,  atropine, 
cocaine,  aconitine)  or  being  converted  into  uncrystallisable  isomers 
{e.g.,  quinine,  cinchonine). 

Concentrated  hydrocliloric  acid,  with  application  of  heat,  converts 
certain  of  the  alkaloids  {e.g.,  morphine,  codeine,  aconitine)  into 
the  so-called  apo-bases,  with  loss  of  the  elements  of  water. 
In  other  instances,  one  or  more  methyl-groups  are  split  off 
(cocaine,  colchicine).     For  colour- reactions,  see  page  145. 

Concentrated  nitric  acid  oxidises  and  decomposes  the  great 
majority  of  the  alkaloids,  nitro-derivatives  being  formed 
in  many  cases  as  intermediate  products.  In  many  cases,  nitric 
acid  yields  more  or  less  characteristic  colour-reactions  with  the 
alkaloids  (page  146). 

Concentrated  sulphuric  acid  decomposes  the  great  majority  of  the 
alkaloids,  the  change  being  sometimes  accompanied  by  interesting 
colour-reactions  (page  145).  On  applying  heat,  charring  frequently 
ensues.  Strychnine  survives  to  some  extent  a  treatment  with 
concentrated  sulphuric  acid  at  100°. 

Reactions  of  the  Alkaloids  with  Alkalies. 

The  fixed  alkalies,  lime,  baryta,  and  ammonia,  liberate  the 
plant-bases  from  their  salts,  and  as  the  free  bases  have,  as  a 
rule,  but  limited  solubility  in  water,  they  are  commonly  pre- 
cipitated when  the  reagent  is  added  to  their  solutions.  The 
base  usually  appears  as  a  white,  very  bulky  or  flocculent  pre- 
cipitate, often  exhibiting  a  crystalline  appearance,  either  at  once 
or  on  standing.  The  precipitates  are  often  hydrated,  and  some- 
times can  only  be  rendered  anhydrous  with  difficulty. 

In  some  cases,  the  plant-bases  when  freshly  liberated  from 
solutions  of  their  salts  by  fixed  alkalies,  alkaline  earths,  or 
ammonia,  are  soluble  in  excess  of  the  precipitant.  Thus  morphine 
and  codeine  dissolve  readily  in  excess  of  caustic  potash  or  soda, 
and  slightly  in  ammonia,  and  morphine  is  also  soluble  in  lime 
and  baryta  water.  Quinine,  but  not  other  cinchona  alkaloids, 
dissolves  in  excess  of  ammonia,  and  strychnine  also  to  a  limited 
extent. 

The  carbonates  of  the  alkali-metals  react  somewhat  peculiarly 
with  the  salts  of  the  alkaloids.  Few  of  the  alkaloids  form 
carbonates,  so  that  the  precipitates  produced  by  alkali-metal 
carbonates  usually  consist  of  the  free  plant-bases.  But  the 
salts  of  some  alkaloids  are  not  precipitated  at  all  by  potassium 
or  sodium  carbonate  {e.g.,  codeine),  and  others  which  are  thus  pre- 
cipitated are  unaffected  by  bicarbonates  (e.^.,  strychnine,  brucine, 
atropine,  veratrine). 


SAPONIFICATION  OF  ALKALOIDS. 


133 


A  few  of  the  alkaloids  give  characteristic  colour-reactions  when 
added  to  fused  caustic  potash.^ 

Saponification  of  Alkaloids. 

Many  of  the  alkaloids,  when  boiled  with  a  fixed  alkali,  baryta, 
or  lime,  undergo  hydrolysis,  with  formation  of  a  base  of  less 
complex  constitution,  and  the  salt  of  an  acid  usually  belonging 
to  the  aromatic  series.  The  change  is  strictly  analogous  to  the 
saponification  of  fats  and  ethereal  salts,  and  can  be  ejffected  by 
boiling  with  dilute  acids  as  well  as  by  alkalies. 

The  following  equations  represent  the  more  important  cases  of 
saponification  of  alkaloids,  and  show  the  products  of  the  reaction 
in  each  case: — 


Aconitine. 

+ 

Kfi 

=     C2eH,,N0,, 

Aconine. 

H- 

C7H6O2 

Benzoic  acid. 

Pseudaconitiue. 

+ 

HgO 

Pseudaconine. 

+ 

Dimethyl-proto- 
catechuic  acid 
(Veratricacid). 

Cs7H5sNO,i 

Veratrine. 

+ 

Bfi 

Verine. 

+ 

Veratric  acid. 

Cevadine. 

+ 

HgO 

=     C,,H,3N0, 

Ccvine. 

+ 

Methyl-crotonic 
acid. 

Narcotine. 

+ 

H2O 

Hydrocotarnine. 

+ 

Meconin. 

C„H,3N03 

Atropine. 

+ 

H2O 

Tropine. 

+ 

Tropic  acid. 

Cocaine. 

+ 

H2O 

Benzoyl-ecgonine. 

+ 

CH,0 

Methyl-alcohol. 

C,,H,,NO, 

Benzoyl-ecgonine. 

+ 

HgO 

Ecgonine. 

+ 

Benzoic  acid. 

Piperine. 

+ 

H2O 

Piperidlne. 

+ 

C12H10O4 
Piperlc  acid. 

CaeH^sNO, 

Sinapine. 

+ 

2H2O 

Choline. 

+ 

CnHxA 

Sinapic  acid. 

*  According  to  W.  L  e  n  z  (Zeitschr.  Anal.  Chem.,  xxv.  29),  out  of  72  alkaloids 
examined,  only  the  following  gave  characteristic  colours  when  fused  with 
caustic  potash,  0*5  milligramme  being  used  in  each  case : — Quinine,  a  grass-green 
and  peculiar  odour;  quinidine,  green,  becoming  yellower  and  finally  brown; 
cinchonine,  brownish-red  to  violet  with  green  edges,  changing  to  bluish-green; 
cinchonidine,  green,  changing  to  grey ;  cocaine,  greenish -yellow,  turning  to 
blue  and  dirty  red  on  stronger  heating. 


134  PIGRATES  OF  ALKALOIDS. 

General  Precipitants  of  Alkaloids, 

Alkaloids  as  a  class  give  precipitates  with  a  considerable 
number  of  reagents,  especially  compounds  of  some  of  the  heavy 
metals.  The  three  precipitants  of  most  general  applicability  are, 
perhaps,  a  solution  of  iodine  in  iodide  of  potassium,  a  solution 
of  phosphomolybdic  acid  (Somnenchein's  reagent),  and  a  solution 
of  the  double  iodide  of  mercury  and  potassium  (Mayer's  reagent); 
but  neither  these  nor  any  other  known  reagent  wiU  precipitate 
every  alkaloid  without  exception.  With  the  exception  of 
tannin,  which  should  be  applied  in  a  strictly  neutral  or  faintly 
alkaline  solution,  the  precipitants  for  alkaloids  should  usually  be 
added  to  a  solution  of  the  base  slightly  acidulated  with  sulphuric 
or  acetic  acid,  but  in  some  cases  (as  in  the  precipitation  of 
certain  picrates)  the  solution  should  be  strongly  acidulated  with 
sulphuric  acid. 

Picric  Acid,  CgH2(N02)3.0H.  Hager^s  Reagent.  When  used  as 
a  test  for  alkaloids,  picric  acid  is  best  employed  in  saturated,  cold, 
aqueous  solution  (1  :  100).  The  alkaloidal  solution  should  be 
rendered  distinctly  acid  with  dilute  sulphuric  acid,  except  in  cases 
where  the  alkaloid  to  be  precipitated  or  sought  for  is  only 
thrown  down  in  neutral  solutions.  The  precipitated  picrates  have 
usually  a  pale  yellow  colour,  and  are  either  crystalline  or  become 
so  after  a  time,  the  forms  in  many  cases  being  characteristic. 

Picric  acid  produces  no  precipitate  in  solutions  (acidulated  with 
sulphuric  acid)  of  aniline,  caffeine,  conine,  morphine,  pseudomor- 
phine,  solanine,  theobromine,  or  the  glucosides ;  and  aconitine, 
atropine,  nicotine,  and  veratrine  are  precipitated  in  concen- 
trated solutions  only.  Atropine  and  morphine  are  precipitated 
from  tolerably  concentrated  neutral  solutions.  Copious  precipitates 
are  produced  by  picric  acid  in  acidulated  solutions  of  berberine, 
colchicine,  delphinine,  emetine,  the  cinchona  alkaloids,  opium 
alkaloids  (except  morphine  and  pseudomorphine),  &c.  Picric 
acid  is  especially  suitable  for  the  precipitation  of  the  cinchona 
alkaloids,  and  Hager  has  devised  a  process  of  assaying  bark 
based  on  that  fact  (see  Assay  of  Cinchona  bark).  Nicotine, 
brucine  and  berberine  may  also  be  conveniently  estimated  by 
picric  acid.  They  should  exist  as  sulphates  in  moderately  acid 
solution,  and  the  picric  acid  be  employed  as  a  cold,  saturated, 
aqueous  solution,  of  which  150  c.c.  will  be  necessary  to  precipitate 
1  gramme  of  the  sulphate  of  a  cinchona  alkaloid,  and  twice  as 
much  for  nicotine  sulphate.  The  following  are  the  limits  of 
dilution  at  which  precipitation  occurs,  and  the  characters  of  the 
precipitates,  according  to  T.  G.  W  o  r  m  1  e  y  : — 


PICRATES   OF   ALKALOIDS. 


135 


Alkaloid. 

Character  op  Precipitate. 

Limit  of 
Precipitation. 

Nicotine,         .       .       . 
Conine,   .... 

Morphine, 

Amorphous,  changing  to   crystal- 
line tufts ;  soluble  in  nicotine. 

Amorphous,  or  liquid  globules  be- 
coming crystalline;  soluble  in 
conine  and  acetic  acid. 

Amorphous. 

1:40,000 
1:500 

1:500 

Codeine,  .... 

Amorphous. 

1:2,000 

Narceine,        .       • 

Amorphous  ;  soluble  in  acetic  acid. 

1:5,000 

Strychnine,     . 
Bnicine,  .... 

Amorphous,      quickly      assuming 

characteristic  crystalline  forms. 

Amorphous,  becoming  crystalline. 

1:20,000 
1:10,000 

Aconitine, 

Amorphous ;  insoluble  in  ammonia. 

1:5,000 

Atropine, 

Veratrine, 

Jervine 

Amorphous,  changing  to  very  char- 
acteristic     crystalline    forms ; 
soluble  in  weak  acid,  including 
acetic. 

Amorphous  ;  soluble  in  weak  acids, 
including"  acetic. 

Amorphous. 

1:1,000 

1:5,000 
1:1,000 

Solanine, 
Qelsemine,      . 

Gelatinous;  soluble   in   excess  of 

picric  acid  solution. 
Amorphous. 

1:1,000 
1:500 

The  alkaloids  may  be  recovered  from  their  picrates  by  mixing 
the  moist  precipitate  with  sodium  carbonate,  drying  the  mixture, 
and  extracting  with  alcohol;  or  the  picrate  may  be  shaken 
with  ammonia  and  a  suitable  immiscible  solvent. 

Tannic  Acid  precipitates  the  great  majority  of  the  vegetable 
alkaloids.  The  precipitates  are  usually  soluble  in  very  weak  acids, 
and  in  ammonia. 

The  tannates  of  aconitine,  brucine,  caffeine,  colchicine,  morphine, 
physostigmine,  and  veratrine  are  dissolved  by  dilute  acetic  acid 
and  tannate  of  quinine  by  somewhat  stronger  acid.  The  tannates 
of  aconitine,  berberine,  (brucine,)  caffeine,  cinchonine,  colchicine, 
narcotine,  papaverine,  thebaine,  solanine,  strychnine,  and  vera- 
trine resist  more  or  less  perfectly  the  action  of  cold  dilute 
hydrochloric  acid.  The  tannates  of  aconitine,  physostigmine, 
quinine,  solanine,  and  veratrine  are  not  redissolved  by  cold  dilute 
sulphuric  acid.  Aconitine,  physostigmine,  and  veratrine  are 
completely  precipitated  by  tannic  acid  from  sohitions  strongly 
acidulated  by  sulphuric  acid,  but  only  partially  from  slightly 
acidulated  solutions. 

An  alkaloid  may  be  recovered  from  its  tannate  by  mixing 
the  moist  precipitate  with  recently  precipitated  lead  carbonate 
or  hydroxide,  drying  the   mixture,  and    boiling    it    with    alcohol 


i36  sonnenschein's  reagent. 

or  other  suitable  solvent,  which,  on  evaporation,  will  often  leave 
the  alkaloid  in  a  characteristic  crystalline  form. 

Phosphomoltbdio  Acid.  Sonnenschein  s  Reagent.  One  of  the 
most  valuable  general  tests  for  alkaloids,  and  reagent  for  separat- 
ing them  from  foreign  matters,  consists  of  a  solution  of  sodium 
phosphomolybdate  in  nitric  acid.  It  is  prepared  by  acidulating  a 
warm  solution  of  ordinary  sodium  phosphate  with  nitric  acid,  and 
adding  an  excess  of  ammonium  molybdate  solution.  The  yellow 
precipitate  is  separated,  washed  with  water,  acidulated  with  nitric 
acid,  and  dissolved  in  a  hot  solution  of  sodium  carbonate.  The 
solution  is  evaporated  to  dryness  and  ignited  at  a  low  red  heat  till 
all  ammonium  salts  are  volatilised,  the  residue  moistened  with 
nitric  acid,  and  again  ignited.  The  product,  consisting  of  p  h  o  s- 
pho-molybdate  of  sodium,  is  dissolved  in  ten  times  its 
weight  of  a  mixture  of  one  measure  of  strong  nitric  acid  (sp.  gr. 
1*42)  with  nine  measures  of  water. 

Sonnenschein's  reagent  gives  yellow,  usually  amorphous,  precipi- 
tates with  nearly  all  alkaloids,  and  as  most  of  the  precipitates  are 
very  insoluble,  a  negative  reaction  with  the  phosphomolybdic  solu- 
tion affords  in  many  cases  a  positive  proof  of  the  absence  of 
alkaloids ;  but,  on  the  other  hand,  ammonium  salts  and  other  non- 
alkaloidal  bodies  are  also  precipitated  by  Sonnenschein's  reagent. 
The  phosphomolybdates  are  decomposed  by  ammonia,  in  some  cases 
with  production  of  a  white  precipitate  of  the  liberated  alkaloid, 
which  can  usually  be  dissolved  by  agitation  with  a  suitable  solvent, 
e.g.^  chloroform,  ether,  benzene,  amylic  alcohol;  but  when  the  alka- 
loid is  readily  oxidisable,  treatment  of  the  phosphomolybdate  with 
ammonia  is  attended  with  the  blue  or  green  coloration  indicative 
of  reduced  molybdic  acid.  This  occurs  in  the  case  of  aconitine, 
aniline,  atropine,  berberine,  codeine,  colchicine,  conine,  morphine, 
nicotine,  physostigmine,  &c.  Where  such  reaction  occurs  the  alka- 
loid is  best  recovered  by  mixing  the  moist  phosphomolybdate 
precipitate  into  a  paste  with  potassium  or  sodium  carbonate,  and 
extracting  with  strong  alcohol. 

Phosphotungstic  Acid,  Scheiblers  Reagent^  is  used  in  a  similar 
manner  to  Sonnenschein's  phosphomolybdic  solution,  and  gives 
very  similar  reactions  with  alkaloids.  It  is  prepared  by  dissolv- 
ing 100  parts  of  sodium  tungstate  and  60  to  80  parts  of  sodium 
phosphate  in  500  parts  of  water,  and  adding  nitric  acid  to  acid 
reaction ;  or  ordinary  sodium  tungstate  may  be  digested  with  half 
its  weight  of  phosphoric  acid  of  1*13  specific  gravity,  and  allowed 
to  stand  for  some  days,  when  phosphotungstic  acid  will  separate  in 
crystals.  Scheibler's  reagent  precipitates  1  :  200,000  solution  of 
Rtrychnine  and  1:100,000  solution  of  quinine.      The  alkaloids 


WAGNER'S  REAGENT.  137 

may  be  recovered  from  their  phosphotungstates  in  the  same  manner 
as  from  their  phosphomolybdates  (see  above). 

Metatungstic  Acid,  Silicotungstic  Acid  (E.  G  o  d  e  f  f  r  o  y),  and 
Phosphoantimonic  Acid  (S  c  h  u  1 1  z  e)  have  been  proposed  as  pre- 
cipitants  of  alkaloids,  but  the  advantages  claimed  for  them  have 
not  led  to  their  general  adoption. 

Bromine  dissolved  to  saturation  in  strong  hydrohromic  acid  has 
been  recommended  as  a  general  reagent  for  alkaloids  by  T.  G. 
W  0  r  m  1  e  y.  It  is  probable  that  hydrochloric  acid  might  be  sub- 
stituted for  the  hydrobromic  acid  without  detriment  to  its  efficacy. 
Wormley^s  Reagent  produces  yellow  amorphous  precipitates  in  solu- 
tions of  many  alkaloids,  and  crystalline  precipitates  with  meconin 
(moderately  strong  solutions),  atropine,  hyoscyamine  and  veratrine, 
the  microscopic  appearance  of  the  precipitate  being  in  each  case 
characteristic.^ 

Iodine  dissolved  in  a  solution  of  potassium  iodide,  Wagner's 
Reagent,  yields  reddish  or  red-brown  precipitates  with  nearly 
all  the  alkaloids,  even  in  very  dilute  solutions.  The  precipitates 
are  formed  more  readily  in  solutions  acidulated  with  sulphuric  acid, 
and  when  applied  under  these  conditions  the  reagent  is  in  effect 
iodised  hydriodic  acid.  Excess  of  the  reagent  should  be  avoided. 
The  quantity  used  should  not  be  sufficient  to  colour  the  solution 
yellow.  Precipitation  is  so  general,  and  occurs  in  such  dilute 
solutions,  that  a  negative  reaction  is  conclusive  proof  of  the  absence 
of  ordinary  alkaloids,  though  precipitation  is  not  conclusive  proof 
of  the  presence  of  an  alkaloid.  The  precipitates  from  aqueous 
solutions  are  usually  amorphous,  though  codeine,  narceine,  and 
strychnine  are  exceptions.  In  alcoholic  solutions  the  precipitates 
are  sometimes  not  formed,  or  are  deposited  very  slowly ;  but  when 
produced,  they  are  often  of  different  character  from  those  yielded 
in  aqueous  solutions,  and  in  some  cases  are  crystalline.  The  pre- 
cipitates are  mostly  poly-iodides  of  the  alkaloids,  the  formulae 
in  some  cases  being  very  complex.  Thus  with  quinine  there  is  first 
a  formation  of  BHI,I;  with  more  of  the  reagent,  BHI,I^  is  obtained ; 
while  in  alcoholic  solution,  in  presence  of  free  sulphuric  acid,  and 

^  C.  L.  B 1  0  X  am  {Chem.  News,  xlvii.  215)  has  pointed  out  that  certain  of 
the  alkaloids  give  characteristic  colour-reactions  when  bromine-water  is  added 
drop  by  drop  to  their  solutions  in  dilute  hydrochloric  acid.  Thus,  brucine 
is  stated  to  yield  a  violet  colour,  and  strychnine  the  same  on  boiling ;  narcotine 
a  rose  pink,  and  the  same  with  quinine,  changed  in  the  latter  case  to  the 
characteristic  grass-green  colour  on  adding  ammonia.  With  excess  of  bromine, 
strychnine,  brucine  and  narcotine  readily  give  yellow  precipitates  ;  whilst 
quinine,  morphine  and  cinchonine  are  only  precipitated  with  difficulty  or  from 
strong  solutions. 


138  dragendorff's  reagent. 

with  an  excess  of  the  reagent,  the  curious  iodo-sulphate  of 
quinine  or  herepathite,  ^ ^,3112^0 ^,2TLI,l^-{-^  aq.,  is  pro- 
duced. Atropine,  strychnine,  berberine,  and  piperine  are  among 
other  alkaloids  giving  characteristic  compounds  with  Wagner's 
reagent.  The  alkaloids  may  be  recovered  from  their  polyiodides 
by  treating  the  precipitate  with  sulphurous  acid,  a  sulphite  and  dilute 
sulphuric  acid,  or  sodium  thiosulphate,  and  then  adding  an  alkali 
and  shaking  with  a  suitable  immiscible  solvent.  Treatment  with 
sodium  thiosulphate  ("  hyposulphite  "),  avoiding  excess,  is  a  con- 
venient means  of  purifying  the  polyiodides  from  co-precipitated 
foreign  matter.  The  reduced  solution  is  filtered  and  again  treated 
with  Wagner's  reagent,  when  the  polyiodide  is  obtained  in  a  con- 
dition of  purity. 

The  strength  of  Wagner's  reagent  may  vary  within  wide  limits. 
Ordinary  decinormal  solution  of  iodine  is  of  suitable  strength,  or  a 
solution  containing  20  grammes  of  iodine  and  50  of  potassium 
iodide  per  litre  may  be  used. 

PoTASSio-IoDiDE  OP  Cadmium,  MarmS's  Reagent,  employed  in 
solutions  acidulated  with  sulphuric  acid,  gives  with  alkaloids  pre- 
cipitates which  are  at  first  amorphous,  but  which  subsequently 
become  crystalline.  They  are  soluble  in  alcohol,  and  in  excess  of 
the  cadmium  solution. 

PoTASSio-IoDiDB  OP  BiSMUTB,  Dvageudorff's  Reagent,  is  best 
made  by  mixing  16  measures  of  the  B.P.  solution  of  citrate  of 
bismuth  with  1  of  strong  hydrochloric  acid  (sp.  gr.  1*16),  and  add- 
ing iodide  of  potassium  equal  in  weight  to  the  hydrochloric  acid 
used  ( J.  C.  T  h  r  e  s  h).  The  resulting  liquid  has  an  orange  colour, 
and  when  added  to  solutions  of  alkaloids,  strongly  acidulated  with 
sulphuric  acid,  forms  orange-red  precipitates,  which  appear  to  be,  in 
most  cases,  wholly  insoluble  in  cold  water.  The  following  are  the 
limits  of  delicacy,  according  to  J.  C.  T  h  r  e  s  h  {Pharm.  Journ.,  [3], 
X.  641,  809) :— Strychnine,  1  in  250,000;  quinine,  1  in  200,000; 
quinidine,  1  in  160,000;  cinchonidine,  1  in  125,000;  narcotine, 
1  in  50,000;  brucine  and  aconitine,  1  in  40,000;  atropine,  1  in 
25,000;  morphine  and  narceine,  1  in  20,000;  codeine,  1  in 
17,500;  apomorphine,  1  in  12,500;  berberine,  1  in  6000  *,. 
caffeine,  1  in  3000.  (See  also  F.  Mangini,  Gazetta^  1882, 
155  ;  Journ.  Chem.  Soc,  xlii.  900.) 

Potassio-Mercurio  Iodide,  Mayers  Reagent,  is  prepared  by 
dissolving  6*775  grammes  of  dry  crystallised  mercuric  chloride^ 
and  25  grammes  of  pure  potassium  iodide  separately  in  water, 
mixing  the  solutions  so  obtained,  and  diluting  the  mixture  to 
1  litre.  The  solution  thus  obtained  is  |  normal,  and  of  con- 
venient strength  for   general   use,  though    of    only  one- half  the 


MAYER'S  SOLUTION.  1S9' 

strength  originally  proposed  by  F.  F.  M  a  y  e  r  ^  (Chem.  Neios,  vii. 
159). 

Mayer's  Solution  precipitates  the  great  majority  of  alkaloids,  and 
in  some  cases  from  very  dilute  solutions.  Applied,  as  it  always 
should  be,  to  solutions  rendered  distinctly  acid  by  hydrochloric  or 
sulphuric  acid,  ammonia  does  not  interfere ;  but  the  solution  to  be 
tested  must  not  be  more  than  slightly  alcoholic,  and  must  not  con- 
tain acetic  acid.  The  precipitates  yielded  by  alkaloids  with 
Mayer's  solution  are  usually  yellowish-white  in  colour,  and  curdy 
or  flocculent.  They  are  more  or  less  soluble  in  alcohol,  ether, 
acetic  acid,  iodides,  and  sometimes  in  an  excess  of  the  reagent. 
Certain  other  organic  matters  besides  alkaloids  are  also  precipitated 
by  Mayer's  solution,  which  therefore  loses  much  of  its  value  when 
applied  to  unpurified  solutions. 

Mayer's  solution  is  chiefly  valuable  as  a  means  of  making  an 
approximate  volumetric  determination  of  the  alkaloid  present  in 
a  solution;  but  unfortunately  the  composition  of  many  of  the 
precipitates  obtained  with  it  varies  to  a  serious  extent  with  the 
concentration  of  the  solution,  the  proportion  of  the  acid  present, 
and  the  excess  of  the  reagent. 

With  strychnine,  the  composition  of  the  precipitate  produced  by 
Mayer's  solution  approximates  to  BHIjHgIg ;  with  morphine  it  ap- 
pears to  be  a  variable  mixture  of  B(HI)4,(Hgl2)3  and  B(HI)g,(Hgl2)3; 
while  with  quinine  the  precipitate  is  not  far  from  the  composition 
B2(HI)3,(Hgl2)3.  These  formulae  refute  the  statement  made  by 
Mayer,  and  reproduced  by  various  writers,  that  the  precipitates  are 
of  definite  composition,  containing  either  1,  2,  or  3  molecules  of 
the  base.  It  has  been  proved  by  Lyons  that  the  precipitates 
nearly  always  contain  a  smaller  proportion  of  mercury  (often 
less  than  three-fourths)  than  has  been  assumed  to  be  present  in 
them.  The  subject  has  also  been  investigated  by  A.  B.  P  r  e  s  c  o  1 1 
{Ghem.  News,  xlv.  114,  123). 

If  Mayer's  reagent  be  added  till  precipitation  ceases,  there  will 
always  be  a  large  excess  of  the  reagent  present.  This  excess  bears 
a  relation  to  the  dilution  of  the  liquid,  and  the  more  dilute  the 
solution,  the  larger  the  volume  of  Mayer's   solution  requisite  to 

*  A.  B.  Prescott  has  pointed  out  {(Jliem.  News,  xlv.  114,  123)  that  the 
proportions  of  mercuric  and  potassium  iodide  used  in  making  Mayer's- 
solution  correspond  to  Hglg  +  eKI,  which  might  be  supposed  to  react  to  form 
2KI,Hgl2  +  2KI  +  2KCl  ;  but  the  reactions  of  the  solution  point  rather  to  the 
formula  KI,Hgl2  +  3KI  +  2KCl.  Nevertheless,  the  proportion  of  potassium 
iodide  cannot  be  greatly  reduced  without  precipitation  of  mercuric  iodide ;  but  a 
permanent  solution  can  be  obtained  with  mercuric  chloride,  potassium  iodide, 
and  potassium  bromide,  used  in  the  proportion  indicated  by  the  formula. 
HgCl2+4KI  +  KBr. 


140  TITRATION  BY  MAYER's   SOLUTION. 

effect  complete  precipitation.  Hence,  in  order  to  render  titration 
with  Mayer's  solution  of  any  value,  it  is  essential  that  the  solutions 
operated  on  shall  be  nearly  of  uniform  strength,  and  that  the  re- 
agent be  added  in  exactly  the  same  manner.  It  is  further  desir- 
able, whenever  possible,  to  make  an  experiment,  side  by  side  with 
the  alkaloidal  solution,  with  a  known  weight  of  the  same  alkaloid 
in  a  state  of  purity,  so  as  to  avoid  all  assumption  as  to  the  be- 
haviour of  the  volumetric  solution  with  the  alkaloid  in  question. 

The  following  is  the  usual  method  of  performing  the  titration 
of  an  alkaloid  with  Mayer's  solution  : — The  solution,  which  should 
be  distinctly  acidulated,  and  contain,  as  a  rule,  0'5  per  cent, 
of  the  alkaloid,  is  treated  with  Mayer's  solution  as  long  as  a  dis- 
tinct precipitate  is  produced.  As  there  is  no  definite  end-reaction, 
and  no  satisfactory  indicator  has  been  as  yet  devised,-^  it  is  necessary 
to  filter  a  portion  of  the  solution  to  ascertain  if  the  precipitation  is 
complete.  A  minute  filter,  about  half  an  inch  in  diameter,  sup- 
ported on  a  ring  of  platinum-wire,  may  be  used.  A  drop  or  two  of 
the  filtered  liquid  ^  is  placed  on  black  glass,  or  on  ordinary  glass  on 
black  paper,  and  a  drop  of  the  volumetric  solution  added  from  the 
burette,  when  the  faintest  turbidity  will  be  readily  perceived.  Before 
the  end  of  the  titration,  all  the  trial-filters  and  test-drops  are  re- 
turned to  the  solution  containing  the  main  quantity  of  the  precipitate. 

The  end  of  the  reaction  is  the  point  at  which  the  Mayer's 
solution  ceases  to  produce  a  precipitate,  and  it  is  worthy  of  notice 
that,  before  this  point  is  reached,  a  condition  of  equilibrium  is 
attained,  in  which  the  solution  is  liable  to  be  precipitated  by  the 
addition  of  either  alkaloidal  solution  or  the  mercury  reagent. 

A,  B.  Lyons  has  investigated  the  behaviour  of  various  alka- 
loids with  Mayer's  solution,  noting  the  effect  of  concentration  and 
the  volume  of  the  reagent  required  to  precipitate  completely  a 
definite  weight  of  alkaloid;  in  addition,  the  volume  required  to 
produce  an  apparent  excess  of  the  mercury  reagent  (so  that  the 
liquid  would  give  a  precipitate  with  more  of  the  alkaloidal  solu- 
tion) ;  and  also  the  actual  excess  of  Mayer's  solution  used,  as  esti- 
mated from  the  quantity  of  mercury  present  in  the  solution. 

Lyon's  results  are  given  in  the  following  table,  reproduced  from 
his  Manual  of  Pharmaceutical  Assaying.  The  mercurial  solution  was 
^  normal,  and  0*1  gramme  of  alkaloid  was  employed  in  each  case  : — 
^  F.  F.  Mayer  proposed  to  ascertain  the  excess  of  the  reagent  by  titrating 
back  with  standard  nitrate  of  silver  solution,  without  filtering,  using  potas- 
sium chromate  as  an  indicator.  As  pointed  out  by  Lupin  ski,  the  sug- 
gestion ignores  the  accumulation  of  chlorides  and  iodides  in  the  solution,  as  also 
the  fact  that  some  of  the  precipitates  react  but  slowly  with  nitrate  of  silver. 

2  A  convenient  form  of  filter-tube  for  the  purpose  has  been  described  by 
F.  C.  J.  Bird  {Pharm.  Jour.,  [3],  xvii.  826). 


PRECIPITATION    BY   MAYERS   SOLUTION. 


141 


Alkaloid. 

Solution. 

Volume  of  Reagent 
in  c.  c. 

Weight  of 

Alkaloid 

precipitated 

Weight  of 

Fresh 
Precipitate 

after 
drying  at 

100°  C. 

For 

For  com- 

Used 

by  1  c.c.  of 

Condition. 

Strength. 

apparent 

plete  pre- 

in 

Reagent. 

excess. 

cipitation. 

excess. 

Acoiiitine, 

1:200 

7-1 

2-0 

•0141 

•180-^190 

Atropine, 

200 

7-b 

131 

8-0 

•0077 

•216- ^220 

... 

400 

6-0 

14-0 

3-5 

•0072 

... 

600 

6-0 

15-0 

3-6 

•0067 

•192--200 

Berberine, 

200 

3-8 

•0263 

... 

400 

3-9 

•0257 

... 

600 

... 

4-6 

.. 

•0218 

•200- ^215 

Brucine, 

NeariV 

200 

.'.'. 

8-0 

i'7 

•0125 

... 

neutral. 

» 

Nearly 
neutral. 

1:400 

... 

8-8 

... 

•0114 

... 

» 

Acid. 

1:400 

... 

9-8 

... 

•0102 

... 

If 

Nearly 

1:600 

... 

9-2 

•0109 

neutraL 

Cinchonidine, 

100 

12-4 

13-8 

1-0 

•0073 

, 

... 

200 

12-4 

13-6 

0-7 

•0074 

•330^*375 

\\ 

'.'!. 

200 

16-6 

2-6 

•0064 

Cincho'nine, 

100 

12-8 

0-8 

•0078 

'.'.'. 

100 

... 

14-0 

1-2 

•0072 

... 

NeutraL 

200 

7-9 

10-8 

•0093 

•333- -345 

Acid. 

200 

8-0 

14-2 

... 

•0071 

... 

M                       •               • 

NeutraL 

400 

8-0 

12-4 

2*4 

•0082 

... 

Acid. 

400 

9-6 

14-18 

... 

•007  to  •OOSO 

... 

Cocaine, 

200 

12-8 

... 

•0078 

•246 

... 

400 

100 

14-4 

4-6 

•0069 

... 

'.'.'. 

600 

16-0 

5-2 

•0063 

... 

Colchicine,    . 

'.'.'. 

200 

s'-2 

9-2 

•0109 

•160 

»» 

... 

400 

4-2 

11-4 

... 

•0088 

... 

... 

600 

5-0 

12-6 

•0080 

... 

Emetine, 

... 

800 

4-0 

14-6 

... 

•0067 

... 

... 

200 

8-0 

9-4 

o-i 

•0106 

•256 

... 

400 

8-8 

iO-2 

10 

•0098 

... 

... 

600 

10-6 

0-6 

•0094 

Gelsemine,    . 

'.". 

200 

5"8 

10-4 

•0096 

•185--200 

. 

... 

400 

6-5 

12-0 

... 

•0084 

Hydrastine,  . 

... 

200 

7-4 

... 

•0135 

•200^'-210 

... 

400 

... 

8-0 

... 

•0125 

... 

... 

600 

... 

8-4 

... 

•0119 

Hyoscyamine, 

... 

200 

8-5 

•0116 

•226-^250 

Morphine,     . 

... 

200 

t'o 

4-91 

... 

•0128 

•190- -240 

400 

8-9 

0-6 

•0110 

Pilocarpine,  . 

... 

200 

4-8 

16-8 

... 

•0060 

•240^-350 

i>           •       • 

... 

200 

20-0 

... 

•0050 

... 

Quinine, 

Neutral. 

200 

li'-e 

16-4 

... 

•0061 

... 

, 

Acid. 

:200 

12-4 

18-0 

... 

•0056 

•310- ^335 

>»                      • 

400 

12-8 

16-8 

..'. 

•0060 

... 

... 

:600 

12-2 

20-0 

•0050 

... 

Strychnine,  . 

... 

.200 

11-0 

6*6 

•0091 

•260-^275 

j> 

Neutral. 

:400 

11-6 

12-0 

... 

•0084 

... 

i>           •       • 

Acid. 

:400 

11-6 

12-2 

... 

•0082 

... 

>i 

... 

:600 

11-2 

11-9 

0-6 

•0087 

... 

From  a  study  of  this  table  by  Lyons,  it  appears  that  while  a 
notable  excess  of  the  reagent  is  generally  needed  to  effect  com- 
plete precipitation,  the  weight  of  the  precipitate  is  in  many  cases 
considerably  below  the  amount  indicated  by  theory.  Better  results 
in  this  respect  are  obtainable  by  allowing  the  liquid  with  the  sus- 
pended precipitate  to  stand  for  some  time.  Lyons  states  that, 
under  these  circumstances,  the  atropine  precipitate  becomes  dense 


142 


PKECIPITATION   BY   MAYER'S  SOLUTION. 


and  crystalline,  and  in  part  adheres  to  the  beaker,  in  which  it  can 
be  washed  by  decantation,  dried,  and  weighed,  the  amount  thus 
found  falling  little  short  of  the  theoretical  weight  of  0'245 
gramme  for  0*100  of  alkaloid. 

The  following  data  showing  the  behaviour  of  alkaloids  with 
Mayer's  solution  are  tabulated  from  the  descriptions  of  D  r  a  g  e  n- 
d  0  r  f  f  {Plant-Analysis  and  Analyse  Chimique  de  quelques  Drogues 
Actives)  :  — 


Milli- 

Correction 

Alkaloid. 

Dilution 
of  Solu- 
tion. 

grams 
of  Alka- 
loid 

Ppted. 
by  1  C.C. 

for  Solu- 
bility. 
Mgrms. 
for  10  C.C. 
Filtrate. 

Observers. 

Conditions  of 
Precipitation. 

Aconitine,     . 

13-45 

0-5 

DragendorflE. 

Pseudaconitine,    . 

... 

19-4 

... 

Atropine, 

1:200 

4-85 

... 

„ 

\  Ample  time  required 
/    for  precipitation. 

>> 

1:380 

4-14 

0-5 

' 

Hyoscyamine, 

1:200 

3-49 

... 

Emitine, 

9-45 

... 

Conine, 

1  :"200 

6-25 

... 

,, 

\  Faintly    acid     only. 
/     KCl  present. 

„ 

... 

2-10 

Mayer. 

Nicotine,      . 

... 

2-02 

... 

Dragendorff. 

rSol.    strongly  acidu- 
i    lated. 

Strychnine,  . 

... 

8-35 

... 

>» 

Brucine, 

... 

8-30 
9-85 

... 

Mayer. 
Dragendorff. 

[•  Sol.  faintly  acid  only. 

Colchicine,   .       '. 

1  :m 

11-65 
15-85 

... 

Kndorff.f  SOL  strongly  acid. 

Morphine,     . 

... 

10-00 

... 

jj 

... 

Narcotine,    . 

... 

10-65 

... 

Veratrine,     . 

14-80 

0-7 

Masing. 

1 

... 

13-50 

Mayer. 

(slightly    acid    solu- 

Sabadilline,  . 

... 

18-70 

0-5 

Masing. 

f    tion. 

Sabatrine,     . 

16-63 

0-4 

'' 

J 

Physostlgmine,     . 

... 

6-87 

1-0 

Berberine,     . 

... 

21-25 

... 

Beach. 

... 

Chelidonine, 

... 

8-37 

... 

Masing, 

... 

Sanguinarine, 

7-42 

,, 

... 

Quinine, 

5-40 

... 

... 

... 

Cinchonine,  . 

5-10 

... 

Hereth  (Pharm.  Record,  1886,  page  209)  has  proposed  an 
improved  method  of  operating  with  Mayer's  solution,  which  allows 
time  for  the  precipitate  to  fully  form.  A  number  of  equal  portions 
of  the  solution  to  be  tested  are  treated  with  volumes  of  the  mercurial 
solution,  regularly  increasing  by  0*1  c.c,  and  allowed  to  stand  eight 
or  ten  hours.  Trial-portions  of  each  mixture  are  then  removed 
and  tested  with  two  drops  of  Mayer's  solution,  when  a  particular 
mixture  will  be  found  to  have  the  mercurial  solution  in  slight 
excess,  while  in  the  previous  mixture  it  is  deficient.  Obviously, 
the  true  amount  lies  between  the  two,  and  it  is  easy  to  ascertain 
the  exact  volume  required. 

Strychnine  and  quinine  are  among  the  alkaloids  yielding  the 
most  insoluble  precipitates  with  Mayer's  solution.     With  atropine 


CHLOROPLATINATES  OF  ALKALOIDS.         143 

:and  morphine  the  reaction  is  far  less  delicate,  and  caffeine  and 
theobromine  are  not  precipitated  at  all. 

Mercuric  Chloride,  HgClg,  gives,  with  certain  alkaloids,  precipi- 
tates of  which  the  crystalline  form  or  melting-point  is  character- 
istic. As  a  rule,  the  precipitates  have  the  constitution  BgHgHgCl^, 
and  are  less  insoluble  than  those  produced  by  Mayer's  reagent. 

Auric  Chloride,  AuClg,  gives  yellow  precipitates  of  alkaloidal 
aurochlorides  or  chloraurates  with  hydrochloric  acid 
solutions  of  many  of  the  alkaloids.  The  double  salts  precipitated 
are  often  very  insoluble.  They  usually  contain  BjHCljAuClg  or 
BHAuCl^,  though  this  formula  is  not  without  exception.  Auric 
chloride  has  the  advantage  that  ammonium  salts  and  the  simpler 
amides  are  not  precipitated  by  it ;  but  the  precipitates  are  unstable, 
the  yellow  colour  in  many  cases  rapidly  changing  to  reddish 
brown,  while  the  supernatant  liquid  occasionally  acquires  an  intense 
red  colour. 

Platinic  Chloride,  PtCl^,  is  a  useful  reagent  for  many  alkaloids, 
with  the  hydrochlorides  of  which  it  combines  to  form  chloro- 
platinates  or  platinochlorides.  In  some  instances, 
these  double  salts  have  the  formula  BHgPtClg,  and  in  other  cases 
they  contain  BgHgPtClg,  while  in  a  few  instances  more  complex 
formulae  have  been  attributed  to  them.  It  is  sometimes  stated 
that  the  alkaloids  containing  Ng  in  the  molecule  form  chloro- 
platinates  of  the  first  formula,  while  in  the  case  of  bases  having 
only  one  atom  of  nitrogen  the  platinum  salts  contain  two  atoms 
of  alkaloid ;  in  other  words,  that  the  ratio  of  N :  Pt  is  con- 
stantly as  2:1.  This,  however,  is  far  from  being  the  case,  for 
alstonine,  gelsamine,  aspidospermine,  paytine,  strychnine,  pilo- 
€arpine,  and  numerous  other  bases  containing  Ng  agree  with  the 
opium  bases,  berberine,  cevadine,  atropine,  and  others  containing  ]S" 
in  forming  platinum  salts  of  the  formula  B2H2PtClg.  In  addition, 
many  of  the  cinchona-bases  form  platinum  salts  of  both  series. 

The  chloroplatinates  of  the  alkaloids  vary  in  colour  from  pale 
yellow,  through  orange  and  red,  to  brownish  red.  They  are 
mostly  sparingly  soluble  in  water,  and  hence  are  usually  formed 
as  precipitates  on  adding  platinic  chloride  to  a  solution  of  the 
alkaloid  acidulated  with  hydrochloric  acid.  The  similar  behaviour 
of  potash  and  ammonia  diminishes  the  value  of  the  test.  Xanthine, 
caffeine,  colchicine  and  pelletierine  are  among  the  alkaloids  not 
precipitated.  Of  the  rest,  the  chloroplatinates  of  quinine,  cin- 
chonine,  morphine  and  strychnine  are  among  those  dissolved 
by  hydrochloric  acid.  The  melting-points  of  the  alkaloidal 
chloroplatinates  are  often  characteristic. 

Potassium    Permanganate,    KMnO^,    produces    characteristic 


144  COLOUR-REACTIONS  OF  ALKALOIDS. 

reactions  with  certain  of  the  alkaloids.  Beckurts  and  List 
have  examined  the  behaviour  of  a  number  of  them,  by  add- 
ing a  decinormal  solution  of  the  reagent,  drop  by  drop,  to  a 
cold  saturated  aqueous  solution  of  the  hydrochloride  of  the  base. 
Immediate  reduction  of  the  permanganate,  with  separation  of 
brown  manganese  oxide,  was  observed  with  the  hydrochlorides  of 
quinine,  cinchonidine,  cinchonine,  cinchonamine,  brucine,  veratrine, 
colchicine,  conine,  nicotine,  aconitine,  physostigmine,  codeine,  and 
thebaine.  The  solutions  of  atropine,  hyoscy amine,  pilocarpine, 
berberine,  piperine,  and  strychnine  were  coloured  red,  the  reagent 
being  only  gradually  reduced. 

With  morphine  hydrochloride  the  permanganate  produced  a 
white  crystalline  precipitate  of  oxydimorphine,  which,  when  filtered 
off  and  dried,  could  be  recognised  by  its  characteristic  reactions. 
Apomorphine  hydrochloride  immediately  reduced  the  reagent,  with 
production  of  an  intense  green  colour. 

On  adding  a  few  drops  of  a  decinormal  solution  of  potassium 
permanganate  to  a  concentrated  solution  of  narceine  hydrochloride 
a  reddish  precipitate  is  immediately  formed,  which  is  very  stable 
in  the  cold  and  in  the  absence  of  an  excess  of  the  reagent,  but  is 
decomposed  on  heating  or  by  addition  of  more  permanganate. 
Solutions  of  papaverine  hydrochloride,  and  of  narcotine  if  diluted 
with  hydrochloric  acid,  at  first  behave  similarly ;  but  the  precipi- 
tates are  much  less  stable  than  narceine  permanganate,  and  soon 
discolour  and  decompose  with  separation  of  brown  manganese  oxide. 

F.  Geisel  (Pharm.  Zeit,  1886,  p.  132)  has  pointed  out  that 
cocaine  gives  a  comparatively  stable  permanganate,  which  forms  a 
purple-violet  precipitate  of  characteristic  microscopic  appearance. 
The  precipitate  forms  only  slowly  in  dilute  solutions,  and  under- 
goes gradual  decomposition. 

Colour-Reactions  of  Alkaloids. 

Many  of  the  alkaloids  give  brilliant,  and  in  some  cases 
characteristic,  colorations  when  treated  with  appropriate  reagents. 
When  possible,  the  reaction  should  be  compared  with  that 
yielded  by  the  pure  alkaloid  treated  side  by  side  with  the 
sample.  The  reagents  which  have  been  proposed  as  colour-tests 
for  alkaloids  are  very  numerous,  and  have  not  always  been  chosen 
or  applied  with  discretion,  nor  with  a  due  regard  to  purity. 
The  colour-reactions  may  be  classified  as: — (1)  Those  produced 
by  dehydrating  agents,  such  as  strong  sulphuric  acid,  phosphoric 
acid,    and    zinc   chloride;^    (2)  those  given  by    oxidising  agents 

^  In  using  zinc  chloride,  Czumpelitz  directs  that  the  substance  to  be 
examined  should  be  first  carefully  dried,  moistened  with  a  solution  of  1  gramme 


COLOUR-TESTS   FOR   ALKALOIDS.  145 

not  of  themselves  yielding  colours,  such  as  nitric  acid,  chlorine, 
bromine,  and  bleaching  powder ;  or  sulphuric  acid  and  oxidising 
agents,  such  as  potassium  chlorate,  perchlorate,  and  perman- 
ganate ;  (3)  those  given  by  oxidising  agents  which  themselves 
yield  a  coloured  product  by  reduction,  such  as  iodic  acid  and 
reagents  containing  chromic,  molybdic,  tungstic,  and  vanadic  acids  ; 
(4)  and  colorations  produced  by  certain  special  reagents,  such  as 
ferric  chloride,  hydrochloric  acid,  sulphuric  acid  and  sugar,i  &c. 

As  a  rule,  the  best  method  of  observing  the  colour-reaction 
of  an  alkaloid  is  to  apply  a  drop  of  the  reagent  by  means  of  a 
pipette  or  glass  rod  to  a  minute  fragment  of  the  solid  alkaloid 
placed  on  a  porcelain  plate  or  in  a  flat  porcelain  dish.  An 
alkaloidal  residue  obtained  by  the  evaporation  in  a  porcelain 
capsule  of  an  alcoholic,  ethereal,  chloroformic  or  other  solution 
may  be  very  conveniently  employed  for  observing  colour-reactions. 

Fused  Caustic  Potash  gives  a  few  interesting  colour-reactions 
with  alkaloids  (see  foot-note,  page  133). 

Concentrated  Hydrochloric  Acid  gives  colour-reactions  with 
a  few  alkaloids.  Thus,  reddish  colours  are  yielded  with  physo- 
stigmine,  sabadilline,  sabatrine,  veratrine,  and  veratroidine ;  and 
a  yellow  with  thebaine.  On  addition  of  chlorine-water  after 
hydrochloric  acid,  berberine  gives  a  red  colour.  Xicotine  yields 
an  amorphous  hydrochloride  and  conine  a  crystalline  salt,  on  evapo- 
rating the  solution  in  hydrochloric  acid. 

Concentrated  Sulphuric  Acid  gives  colour-reactions  with  a 
number  of  alkaloids,  the  coloration  varying  with  the  degree  of 
heat  applied.  The  following  reactions  have  been  observed  when 
the  acid  is  dropped  on  to  the  solid  alkaloid,  without  applying 
heat : — No  colour^  or  a  faint  straw  tint  only,  is  yielded  by 
pure  aconitine,  atropine,  caffeine,  chelonidine,  cinchonidine,  cocaine, 
codeine,  hyoscine,  hyoscyamine,  gelsemine,  morphine  (purple  to 
brown  on  warming),  nicotine,  pilocarpine,  quinine,  quinidine, 
staphisagrine,  strychnine,  and  theobromine.  Yellowish  colorations 
are  given  by  colchicine,  gnoscopine,  jervine,  and  by  many  other 
alkaloids  in  presence  of  impurities.  Reddish  colours  are  pro- 
duced   either    immediately   or    gradually,   with   impure   aconitine, 

melted  zinc  chloride  in  30  c.c,  of  water,  and  dried  again.  If  thus  treated, 
strychnine  takes  a  scarlet  colour,  thebaine  a  y(41ow,  narceine  an  olive-green, 
delphinine  a  red-brown,  berberine  a  yellow,  veratrine  a  red,  quinine  a  pale 
yellow,  digitaliu  a  maroon,  salicin  a  violet-red,  santonin  a  violet-blue,  and 
cubebin  a  purple.  The  presence  of  brucine  prevents  the  coloration  of  strych- 
nine, the  tinge  produced  being  a  dirty  yellow  {Giornale  Farm.  Chim.  ;  Jour, 
Chem.  Soc,  xlii.  340). 
1  Information  respecting  this  test  will  be  found  under  "morphine." 
VOL.   III.  PART  II.  K 


146  COLOUR-TESTS   FOR    ALKALOIDS. 

apomorphine,  briicine  (pale  rose),  cocaine  (impure),  conine  (pale 
red),  gelsemine  (impure),  meconidine,  narceine  (changing  to  black), 
narcotine  (yellowish-red,  changing  to  violet  and  blue),  physostig- 
mine,  rhceadine,  sabadilline,  sabatrine,  solanine,  taxine,  thebaine, 
veratrine,  and  veratroidine.  Bluish  colorations  are  yielded  by 
cryptopine,  curarine  (after  a  time),  and  papaverine.  Greenish  colours 
are  given  by  beberine,  berberine,  emetine  (brownish  to  green), 
piperine,  pseudomorphine,  and  sometimes  by  rhceadine. 

Some  characteristic  changes  of  colour  can  be  obtained  by 
gradually  warming  the  capsule  in  which  the  test  is  being  made, 
by  placing  it  over  a  small  beaker  of  boiling  water.  The  ultimate 
result  is  usually  browning  and  charring  of  the  alkaloid,  but  the 
intermediate  reactions  are  often  of  value. 

Many  substances  besides  alkaloids  give  more  or  less 
brilliant  colour-reactions  with  strong  sulphuric  acid.  Thus  red 
colorations  (often  of  a  brilliant  hue)  are  obtained  with  amygdalin, 
columbin,  cubebin,  elaterin,  hesperidin,  phloridzin,  populin,  salicin, 
sarsaparillin,  senagin,  smilacin,  syringin,  and  many  varieties  of 
tannin. 

In  applying  sulphuric  acid  as  a  colour-test  for  alkaloids,  it 
must  be  remembered  that  the  presence  of  a  very  minute  quantity 
of  nitric  acid,  often  present  as  an '  impurity,  greatly  modifies  the 
colorations  produced  by  many  of  the  alkaloids.  Thus,  if  the 
treatment  with  sulphuric  acid  (without  applying  heat)  be  followed 
by  the  addition  of  a  very  minute  quantity  of  nitric  acid  (at  the 
and  of  a  glass  rod  drawn  out  to  a  point),  or  a  minute  fragment 
of  solid  potassium  nitrate,  the  following  reactions  will  be  ob- 
tained :  ^  No  colour  with  atropine,  caffeine,  cinchonidine,  cin- 
chonine,  nicotine,  pilocarpine,  quinidine,  quinine,  staphisagrine, 
strychnine,  or  theobromine ;  red  coloration  with  brucine,  curarine, 
narcotine  (reddish  violet  or  blood-red),  physostigmine,  sabadilline, 
thebaine,  and  veratrine  (gradual  change  to  cherry-red).  Special 
and  peculiar  changes  of  colour  are  produced  by  morphine,  codeine, 
and  colchicine,  and  are  described  in  the  respective  sections  on 
these  alkaloids. 

Strong  Nitric  Acid,  of  1*40  to  1'42  specific  gravity,  gives 
more  or  less  characteristic  colour-reactions  with  a  number  of  alka- 
loids.    ^  drop  of  the  acid  should  be  applied  by  means  of  a  glass 

^Erdmann  applies  this  test  by  mixing  6  drops  of  nitric  acid  of  1  "25 
specific  gravity  with  100  c.c.  of  water,  and  adding  10  drops  of  the  dilute 
acid  so  obtained  to  20  grammes  of  sulphuric  acid.  From  8  to  10  drops 
of  the  solution  so  prepared,  or  Erdmann's  Reagent,  is  added  to  1  or  2  milli- 
grammes of  the  solid  to  be  tested,  and  the  colour  observed  after  20  to  30 
minutes. 


frohde's  reagent.  147 

rod  to  a  minute  fragment  of  the  alkaloid,  or  to  a  residue  left  on 
evaporating  a  solution  on  white  porcelain.  No  coloration  is  yielded 
by  aconitine  (when  pure),  atropine,  caffeine,  cinchonidine,  cincho- 
nine,  conine,  gelsemine  (impure,  greenish),  quinidine,  quinine, 
strychnine,  or  theobromine.  YelloicisU  colours  are  obtained  with 
impure  aconitine  (colour  varies  from  yellow  to  red  and  brown), 
codeine  (orange-yellow),  morphine  (yellow  to  red),  narceine,  narco- 
tine,  papaverine  (orange),  piperine  (orange),  rhoeadine,  sabadilline 
(yellow),  thebaine,  and  veratrine.  Red  shades  are  produced  by 
impure  aconitine  (colour  varies  from  yellow  to  red  and  brown), 
apomorphine,  beberine  (red  to  red-brown),  berberine  (red-brown), 
brucine  (blood-red),  papaverine  (orange-red),  pseudomorphine 
(orange-red),  and  physostigmine  (gradually).  Gelsemine  yields  a 
deep  bluish  green  residue  on  evaporation.  Blue  colours  are  said 
to  be  given  by  colchicine  and  solanine ;  and  by  the  glucosides 
igustrin  and  syringin. 

SuLPHOMOLYBDic  AciD,  Fvohdes  Reagent,  affords  one  of  the 
most  useful  of  the  oxidation-tests  for  alkaloids ;  but  it  must  be 
borne  in  mind  that  the  colours  produced  are  in  great  measure 
those  of  the  lower  oxides  of  molybdenum,  and  that  various  other 
bodies  besides  alkaloids  readily  reduce  molybdic  acid  with  forma- 
tion of  these  coloured  oxides.  The  reagent  itself,  if  strongly 
heated,  acquires  a  blue  coloration  from  reduction  of  the  molybdic 
acid.  Frohde's  reagent  is  prepared  by  dissolving  6  milligrammes  of 
molybdic  acid  or  molybdate  of  ammonium  in  each  1  c.c.  of  strong 
sulphuric  acid.  No  colour  is  produced  with  atropine,  caffeine, 
cinchonidine,  cinchonine,  conine,  delphinine,  hyoscine,  hyoscyamine, 
nicotine,  strychnine,  or  theobromine.  Yellowish  colorations  are 
given  by  aconitine,  colchicine,  and  piperine.  Reddish  shades  of 
colour  are  produced  by  brucine,  emetine  (red,  changing  to  green), 
narceine  (red,  changing  to  blue),  sabadilline  (reddish  violet),  solanine, 
thebaine  (orange),  and  veratrine  (gradual  production  of  a  cherry-red 
colour).  Bluish  colours  are  given  by  codeine  (gradual  production  of 
deep  blue),  morphine  (violet-blue,  then  dirty  green,  changing  to 
deep  blue),  narceine  (yellowish  brown,  changing  to  red  and  blue), 
staphisagrine,  (violet-brown).  Greenish  colorations  are  produced 
by  apomorphine  (green  to  violet),  beberine  (brown-green),  ber- 
berine (brown-green),  emetine  (red,  changing  to  green,  and  turned 
blue  by  hydrochloric  acid),  quinine  (pale  green),  and  quinidine 
(pale  green). 

Of  non-alkaloidal  bodies,  colocynthin  gives  slowly  a  cherry-red 
colour ;  elaterin,  a  yellow ;  phloridzin,  gradually,  blue ;  populin, 
violet ;  salicin,  violet  to  cherry-red ;  and  syringin,  a  blood-red  to 
violet-red  coloration. 


148  COLOUR-TESTS   FOR  ALKALOIDS. 

SuLPHOVANADio  AciD  has  been  recommended  byF.  Kundrdt 
{Chem.  Zeit.,  xiii.  265  ;  Jour.  Soc.  Chem.  Ind.,  viii.  421)  as  a 
colour-test  for  alkaloids.  The  reagent  is  prepared  by  dissolving 
0"1  gramme  of  ammonium  vanadate  in  10  c.c.  of  strong  sulphuric 
acid.  It  is  stated  to  give  the  following  reactions,  many  of  which 
are  due  to  the  production  of  the  coloured  lower  oxides  of  vanadium, 
and  hence  are  likely  to  vary  with  the  proportions  of  the  reagent 
and  alkaloid  employed.  No  coloration  is  produced  by  cafifeine  or 
nicotine.  Brown  by  aconitine  (light  coflfee-brown),  codeine  (greenish 
brown,  becoming  darker),  morphine,  narceine  (changing  to  dirty 
bluish  violet,  then  gradually  reddish  brown),  piperine  (intense  red- 
dish brown  to  black),  kairine  (dirty  pink,  quickly  changing  to  dirty 
light  brown  and  brownish  green),  solanine  (cotfee-brown,  changing 
at  the  edge  to  purple  and  in  the  centre  to  dirty  green,  and  very 
gradually  becoming  an  intense  violet  jelly).  Bed  colorations  are 
given  by  atropine  (changing  to  yellowish  red  and  yellow),  brucine 
{intense  blood-red,  gradually  fading),  narcotine  (blood-red  or 
purple),  and  veratrine  (brownish  red,  changing  to  reddish  violet). 
Yellowish  or  orange  colours  are  produced  by  cinchonine  (changing 
to  green),  cocaine  (orange,  froths  on  dissolving),  physostigmine 
(greenish  yellow,  then  purple,  finally  yellow-brown),  and  quinine 
(changing  to  bluish  green  and  greenish  brown).  Green  colorations 
are  produced  by  colchicine  (changing  to  greenish  brown  and  cofiFee- 
brown),  conine  (intense  green,  changing  to  brown),  and  quinidine 
(faint  bluish  green).  Blue  reactions  are  produced  by  antipyrine 
(greenish  blue,  gradually  becoming  bluer),  and  apomorphine  (dark 
violet  blue,  rapidly  changing  through  dirty  green  to  reddish  and 
light  brown).  Violet  colorations  are  given  by  papaverine  (gradually 
changing  to  bluish  green  and  orange-green),  and  strychnine  (bluish 
violet,  changing  to  reddish  violet,  purple,  and  brilliant  red). 

Of  colorations  with  non-basic  principles  the  following  have  been 
recorded: — Antifebrin,  purple,  rapidly  changing  to  brown;  digi- 
talin,  intense  brown,  with  reddish  shade;  and  salicylic  acid, 
brownish  green.  Picrotoxin  and  santonin  give  no  coloration  with 
sulphovanadic  acid. 

Ferric  Chloride  gives  a  few  characteristic  colorations,  the 
most  important  being  the  blue  reaction  with  morphine  and  the 
blood-red  with  antipyrine  (page  35).  A  freshly-made  mixture  of 
ferric  chloride  and  potassium  fei'ricyanide  (free  from  ferrocyanide), 
both  in  aqueous  solution,  has  a  yellowish  brown  colour ;  but  in 
presence  of  certain  alkaloids  it  is  immediately  coloured  blue  (or 
green)  owing  to  the  production  of  Prussian  blue.  This  reaction 
was  at  first  regarded  as  characteristic  of  the  ptomaines  or 
cadaveric  bases,  but  it    is    produced    by    any    readily    oxidisable 


PHYSIOLOGICAL  TESTS   FOR   ALKALOIDS.  l49 

alkaloid,  and  hence  is  given  immediately  by  morphine,  aconitine, 
physostigmine,  &c.,  and  after  a  short  time  by  hyoscyamine, 
emetine,  colchicine,  nicotine,  and  many  of  the  tar- bases. 

Oxidation -COLOUR -REACTIONS  are  also  produced  by  reagents 
having  a  more  powerful  oxidising  action  than  the  foregoing.  Thus 
strong  sulphuric  acid  may  be  employed  in  conjunction  with 
potassium  nitrate,  chlorate,  perchlorate,  permanganate,  bichromate, 
and  ferricyanide ;  or  with  metallic  peroxides,  such  as  those  of  man- 
ganese (Mn02),  lead  (PbOg),  ruthenium  (RuOg),  uranium  (UgOg), 
and  cerium  (CegOJ.  The  most  important  of  the  colour-reactions 
obtained  with  such  reagents  are  those  yielded  by  strychnine,  cura- 
rine,  gelsemine  and  aniline,  which  are  fully  described  elsewhere. 

Physiological  Tests  for  Alkaloids. 

A  large  number  of  the  natural  alkaloids,  if  not  an  actual 
majority,  have  well-marked  poisonous  characters.  The  symptoms 
produced  are  of  the  varied  description,  ranging  from  the  nar- 
cotism of  morphine  to  the  paralysis  of  conine  and  the  tetanus  of 
strychnine. 

In  making  experiments  on  animals  it  is  often  advantageous  to 
administer  the  poison  by  hypodermic  injection  of  a  solution  of 
alkaloid  in  water,  or  weak  spirit  acidulated  with  acetic  acid.  Such 
a  plan  obviates  the  loss  of  the  poison  by  vomiting,  which  some- 
times eliminates  the  greater  part  of  the  poison  from  the  system. 
On  the  other  hand,  the  subcutaneous  injection  of  small  animals  is 
open  to  certain  obvious  objections,  and  in  many  cases  internal 
administration  may  be  advantageously  substituted  for  it,  especially 
if  the  animal  employed  be  a  rabbit  or  guinea-pig,  and  hence  not 
liable  to  vomit.  In  many  instances,  such  animals  are  hopelessly 
large,  and  mice,  small  birds,  or  frogs  must  be  employed.  W  y  n  t  e  r 
B 1  y  t  h  has  used  blowflies  with  success  in  some  cases,  and  occasion- 
ally fish  are  of  service.  When  the  poison  is  to  be  given  internally, 
the  extract  or  very  strong  solution  should  be  made  up  into  one  or 
more  small  pills  with  oatmeal,  which  the  animal  is  either  induced 
to  eat  or  forced  to  swallow.  In  the  case  of  linnets  and  other  small 
birds,  a  drop  of  the  liquid  to  be  tested  should  be  introduced  into 
the  open  beak  by  means  of  a  pipette  or  feather. 

In  some  cases,  physiological  tests  may  be  advantageously  made 
on  human  subjects.  Besides  observing  the  bitter  taste  possessed 
by  most  alkaloids,  the  tingling  sensation  produced  on  the  tongue 
by  aconitine  and  cocaine  can  be  thus  detected. 

A  marked  physiological  characteristic  of  many  of  the  alkaloids, 
sufficiently  striking  in  some  cases  to  serve  as  actual  evidence  of 
their  presence,  is  their  effect  on  the  pupil  of  the  eye.     The  test  is 


150       EFFECT  OF  ALKALOIDS  ON  THE  PUPIL. 

generally  made  by  placing  a  drop  of  the  alkaloidal  solution  to  be 
examined,  as  nearly  neutral  as  possible,  on  the  eye  of  a  rabbit, 
dog  or  cat,  when,  in  a  time  varying  from  a  few  minutes  to  about 
half  an  hour,  a  marked  contraction  or  dilation  of  the  pupil  will  be 
observed. 

A.  The  pupil  is  dilated  by : — 

1.  Atropine  and  belladonna  ;  hyoscyamine  and  h  y  o- 

seine,  and  preparations  of  henbane  and  stamonium ; 
s  0 1  a  n  i  n  e  ;  and  extracts  from  solanaceous  plants 
generally. 

2.  Cocaine,  and  preparations  of  coca. 

3.  Conine,  and  preparations  of  hemlock  and  other  umbel- 

liferous plants. 

4.  C  y  t  i  s  i  n  e,  and  preparations  of  laburnum. 

5.  Digital! n,  and  preparations  of  foxglove. 

6.  Gelsemine,    and    preparations    of   gelsemium    (yellow 

jesamine). 

7.  Sparteine,  and  preparations  of  broom. 

8.  Yeratrine,  jervine,  and  preparations  of  hellebore. 

9.  Hydrocyanic  acid  and  cyanides. 

Mydriasis,  or  dilation  of  the  pupil,  is  so  striking  a  characteristic 
of  atropine  and  the  isomeric  and  associated  bases  that  these  are 
often  grouped  together  as  the  "mydriatic  alkaloid  s."  The 
mydriasis  is  only  observed  in  the  eye  to  which  the  alkaloid  is 
applied. 

B.  The  pupil  is  contracted  by  : — 

1.  Morphine,  and  other  opium  alkaloids  and  preparations 

of  opium. 

2.  Aconitine,  and  preparations  of  aconite  and  other  mem- 
bers of  the  RanunculacecB. 

3.  Physostigmine,    and   preparations    of    the    Calabar 

bean. 

4.  Strychnine,    brucine,    and    preparations    of    nux 

vomica. 

A  similar  effect  on  the  pupil  is  produced  by  the  poisons  when 
taken  internally  or  hypodermically  in  sufficient  quantities.  Some- 
times, as  in  the  case  of  morphine  and  preparations  of  opium, 
the  pupils  are  contracted  during  the  early  stages  of  the  poisoning, 
but  dilated  subsequently,  especially  after  death.  Nicotine  and 
preparations  of  tobacco  in  some  cases  cause  contraction,  and  in 
others  dilation,  of  the  pupil.  In  poisoning  with  aconitine  alter- 
nate contraction  and  dilation  of  the  pupil  is  sometimes  observed. 


EXTRACTION  OF  ALKALOIDS. 


151 


ISOLATION  AND  PURIFICATION  OF  ALKA 
LOIDS. 

The  vegetable  alkaloids  are  found  in  all  parts  of  plants,  and  in 
many  cases  constitute  their  characteristic  active  principles.  It 
must  not  be  assumed  that  the  active  principle  is  necessarily  of  an 
alkaloidal  character,  though  plants  and  plant-products,  which  act 
primarily  on  the  nervous  system,  producing  tetanus,  paralysis,  or 
narcosis  (e.^.,  nux  vomica,  aconite,  opium),  owe  their  activity,  as  a 
rule,  to  the  presence  of  an  alkaloid.  On  the  other  hand,  in  plants 
which  act  primarily  on  the  muscular  system  (e.g.,  digitalis),  the 
active  principle  is  usually  of  a  non-alkaloidal  character.  Where 
the  action  of  the  plant  is  emetic,  cathartic,  or  purely  astringent, 
the  active  principle  is  usually  of  a  neutral  or  resinous  character; 
but  this  statement  has  some  marked  exceptions,  for  ipecacuanha, 
a  typical  emetic,  owes  its  activity  to  the  alkaloid  emetine. 

An  alkaloid  never  exists  in  a  plant  in  a  free  state.  It  is  most 
frequently  present  as  a  salt,  often  an  acid  salt,  of  some  organic 
acid,  especially  malic  acid  or  one  of  the  varieties  of  tannic 
acid.  In  some  instances  the  acid  with  which  the  alkaloid  is 
united  is  peculiar  to  the  plant  in  question,  as,  for  instance, 
meconic  acid  in  opium,  quinic  acid  in  cinchona  bark,  and 
igasuric  acid  in  nux  vomica.  In  other  cases  the  alkaloid  is 
combined  with  an  inorganic  acid,  as  is  the  case,  in  part  at  least, 
with  the  morphine  in  opium.  The  natural  forms  of  combina- 
tion of  the  alkaloids  are  almost  invariably  readily  soluble  both  in 
water  and  in  alcohol,  but  insoluble  in  ether. 

The  general  action  of  solvents  on  the  leading  constituents  of 
plants  will  be  seen  from  the  following  table,  which  will  also  serve 
to  indicate  the  nature  of  the  bodies  likely  to  be  co-extracted  with 
the  alkaloid  when  the  respective  solvents  are  employed : — 


Water. 

Alcohol. 

1 
Ether. 

Alkaloidal  salts,     .       . 

Soluble. 

Soluble. 

Insoluble. 

Other  salts  of  inorganic 

acids, 
Other  salts  and  organic 

acids. 
Free  organic  acids, 

Mostly  soluble. 

Mostly  insoluble. 

Insoluble. 

Soluble. 

Soluble. 

Mostly  insoluble. 

Soluble. 

Soluble. 

Mostly  insoluble. 

Tannins  and   colouring 

matters, 
Sngars,    .... 

Soluble, 

Soluble. 

Variable. 

Soluble. 

Soluble. 

Insoluble. 

Gums  and  pectous  bodies, 

Soluble. 

Mostly  insoluble. 

Insoluble. 

Albuminoids,  &c., 

Soluble. 

Insoluble. 

Insoluble. 

Starch,     .       . 

Soluble    in   hot 
water. 

Insoluble. 

Insoluble. 

Cellulose, 

Insoluble. 

Insoluble. 

Insoluble. 

Resins,    . 

InsoluV)le. 

Soluble. 

Variable. 

Fixed  oils,       . 

Insoluble. 

Sparingly  soluble. 

Soluble. 

Essential  oils, 

Insoluble. 

Soluble. 

Soluble. 

Chlorophyll,   . 

Insoluble. 

Soluble. 

Soluble. 

162  EXTRACTION  OF  ALKALOIDS. 

Alcohol  is  the  solvent  best  adapted  for  the  extraction  of 
alkaloids  from  plants,  which  should,  of  course,  be  reduced  to  a 
suitable  condition.  The  treatment  may  with  advantage  be  re- 
peated several  times,  the  residue  being  well  pressed  between  each 
exhaustion,  which  is  preferably  effected  by  a  percolator,  or  some 
equivalent  arrangement.  In  the  final  extraction,  the  addition 
of  a  little  sulphuric  or  tartaric  acid  is  often  an  advantage, 
but  the  amount  of  acid  used  should  be  very  limited,  and  its 
employment  is  vetoed  in  the  case  of  readily  changeable  alkaloids. 
Hot  water  may  be  substituted  for  alcohol  in  some  cases.  When 
alcohol  has  been  used  for  the  extraction,  it  should  be  removed 
partially  or  wholly  by  gentle  evaporation  before  proceeding  to 
the  next  stage  of  the  treatment. 

The  method  to  be  adopted  for  the  isolation  of  the  alkaloid 
from  the  infusion  or  tincture  obtained  depends  much  on  its  nature, 
and  the  object  of  the  experiment.  Extraction  by  immiscible 
solvents  permits  the  detection  of  small  quantities  of  alkaloids,  which 
defy  methods  based  on  precipitation,  and  hence  this  principle  is 
very  valuable  in  toxicological  investigations ;  but,  on  the  other 
hand,  the  alkaloids  so  extracted  are  usually  less  pure  than  when 
isolated  by  other  means. 

Where  it  is  intended  to  attempt  the  separation  of  the  alkaloid 
by  conversion  into  an  insoluble  or  nearly  insoluble  compound,  a 
variety  of  precipitants  are  available,  each  one  of  which  has  special 
advantages  in  particular  cases.  But  before  resorting  to  these 
general  precipitants,  it  is  desirable,  and  in  many  cases  absolutely 
necessary,  to  remove  from  the  liquid  as  much  as  possible  of  the 
inert  organic  matters.  The  best  reagent  for  this  purpose  is  lead 
acetate,  which  should  be  added  gradually  to  the  previously 
neutralised  liquid,  as  long  as  a  precipitate  continues  to  be  produced, 
avoiding  the  use  of  any  considerable  excess  of  the  reagent.  The 
precipitate  having  been  filtered  off,  the  filtrate  should  be  treated 
with  basic  acetate  of  lead,  which  in  many  cases  will  produce  a 
further  precipitate,  to  be  removed  by  the  filter  as  before.  On 
adding  ammonia  to  the  filtrate,  a  third  precipitate  will  frequently 
be  produced,  but  it  must  be  remembered  that  cinchonine  and  other 
sparingly  soluble  alkalies  are  liable  to  be  thrown  down  at  this 
stage.^  (On  this  account  it  is  undesirable  to  add  basic  acetate  of 
lead  and  ammonia  at  once,  and   filter  off  the  joint  precipitate.) 

^  The  threefold  treatment  with  neutral  lead  acetate,  basic  lead  acetate, 
and  ammonia  in  presence  of  lead  acetate  causes  the  precipitation  of  tannins  ; 
most  vegetable  acids  {e.g.,  malic,  tartaric,  oxalic)  ;  albuminoids,  starches,  and 
gums  ;  many  glucosides,  sugars,  and  dextrin  ;  and  the  majority  of  colouring 
matters. 


ISOLATION   OF  ALKALOIDS.  153 

The  liquid,  whicia  should  smell  distinctly  of  ammonia,  is  next 
evaporated  at  a  gentle  heat  till  the  odour  of  ammonia  has  dis- 
appeared, when  the  excess  of  lead  is  precipitated  by  a  stream 
of  sulphuretted  hydrogen  or  the  addition  of  a  moderate  excess  of 
dilute  sulphuric  acid.  Of  these  plans,  the  first  is  much  to  be 
preferred.  The  lead  sulphide  often  carries  down  with  it  a  notable 
quantity  of  colouring  matter,  otherwise  difficult  to  remove,  and  the 
excess  of  sulphuretted  hydrogen  is  easily  got  rid  of  by  concen- 
trating the  filtrate  at  a  gentle  heat.  When  sulphuric  acid  has  been 
employed  to  precipitate  the  lead,  the  filtrate  should  be  carefully 
neutralised  before  attempting  to  further  concentrate  the  liquid, 
otherwise  the  alkaloid  may  suffer  partial  or  complete  decom- 
position. 

The  alkaloidal  solution,  having  been  purified  by  the  foregoing 
treatment,  may  be  treated  v/ith  one  of  the  general  reagents  for 
alkaloids,  the  choice  of  which  will  necessarily  depend  on  the 
nature  of  the  base  supposed  to  be  present.  Where  this  is 
unknown,  preliminary  tests  with  various  precipitants  should  be 
made  on  small  aliquot  fractions  of  the  solution.  Although  other 
reagents  may  be  preferable  in  particular  cases,  the  choice  will 
generally  lie  between  one  of  the  following  precipitants : — 

1.  A  fixed  alkali,  carbonate  of  alkali-metal,  lime,  or  ammonia; 

suitable  for  precipitating  morphine,  the  cinchona  alka- 
loids, the  aconite  bases,  &c. 

2.  Picric  acid  (page   134);   very  suitable   for  precipitating 

the  cinchona  bases,  emetine,  berberine,  and  veratrine. 

3.  Tannic  acid  (page  135). 

4.  Phospliotungstic    or    phospliomolyhdic    acid    (page    136); 

available    for    the    great    majority    of    alkaloids,    and 
especially  for  strychnine. 

5.  Iodised  iodide  of  potassium  (page   137),  which  produces 

very  insoluble    precipitates  with  the   great  majority  of 
alkaloids. 

6.  Mayer's  solution  (potassio-iodide  of  mercury)  (page  139); 

valuable  for  precipitating  emetine  and  the  opium  bases. 

With  the  exception  of  tannic  acid,  which  should  be  applied 
to  the  neutral  or  even  faintly  alkaline  solution  of  the  alkaloid, 
the  reagent  should  be  added  to  the  acidulated  solution,  sulphuric 
acid  being  the  most  suitable  acid  to  bring  the  liquid  to  the 
proper  condition.  In  most  cases  precipitation  is  tolerably  rapid, 
but  it  is  desirable,  as  a  precaution,  to  wait  24  hours  before 
proceeding  with  the  filtration.  This  is  especially  necessary  perhaps 
in    the    case    of   precipitants    1    and    2.     The    alkaloid   may   be 


154  USE  OF  IMMISCIBLE  SOLVENIS. 

recovered  from  the  precipitate  in  the  manner  described  on  page 
135  e^  seq. 

As  a  rule,  the  salts  of  the  alkaloids  are  not  soluble  in  immiscible 
solvents,  and  hence  when  the  acidulated  solution  of  an  alkaloid  is 
agitated  with  chloroform,  ether,  petroleum  spirit,  benzene,  or  amylic 
alcohol,  tlie  solvent  does  not  remove  the  base  from  the  aqueous 
liquid.  This  behaviour  broadly  distinguishes  alkaloids  from 
glucosides;  but,  owing  chiefly  to  their  weak  basic  character 
and  the  instability  of  their  salts,  caffeine,  colchicine,  delphinine, 
narcotine,  papaverine,  thebaine,  and  theobromine  are  partially  or 
wholly  removed  from  their  acidulated  solutions  on  agitation  with 
chloroform,  while  amylic  alcohol  is  stated  to  extract  berberine  and 
veratrine  in  addition  to  the  above  bases. 

Extraction  by  Immiscible  Solvents. 

The  behaviour  of  the  alkaloids,  when  their  acid  and  alkaline 
solutions  are  agitated  with  immiscible  solvents,  is  of  the  highest 
practical  value  for  their  isolation  and  identification.-^ 

The  immiscible  solvents  used  for  the  extraction  of  alkaloids,  &c., 
should  be  free  from  any  trace  of  fixed  or  difficultly  volatile  organic 
matter.  This  is  best  ensured  by  shaking  the  solvent  with  water 
slightly  acidulated  with  sulphuric  acid,  separating  the  aqueous 
liquid,  and  redistilling  the  immiscible  solvent  at  a  moderate  tem- 
perature— rejecting  the  last  portion.  The  distillate  should  then 
be  agitated  with  water  rendered  faintly  alkaline  by  caustic  soda, 
and  indeed  may  be  advantageously  kept  in  contact  with  faintly 
alkaline  water.  The  agitation  with  water  is  essential  in  the  case 
of  solvents  liable  to  certain  alcohol  (e.g.,  ether,  chloroform,  amylic 
alcohol),  the  presence  of  which  might  seriously  modify  their 
action. 

In  using  immiscible  solvents,  it  must  be  borne  in  mind  that 
extraction  is  never  theoretically  perfect  with  a  single  treatment. 
The  dissolved  body  is  distributed  between  the  two  solvents  in 
proportions  which  are  probably  dependent  on  the  relative  solu- 
bility of  the  substance  in  the  two  media,  and  the  relative 
quantities  of  the  two  media  employed.  Thus,  it  may  be  sup- 
posed that  if  a  substance  be  99  times  more  soluble  in  chloroform 
than  in  water,  and  its  aqueous  solution  be  shaken  with  an  equal 

^  The  principle  appears  to  have  been  first  adopted  by  Otto  in  1856,  who 
employed  ether  in  his  modification  of  S  t  a  s '  process  for  the  detection  of 
poisonous  alkaloids.  In  1856,  Rodgers  and  Gird  wood  employed  the 
method  with  chloroform,  and  in  1861  Uslar  and  Erdmann  recommended 
the  use  of  amylic  alcohol.  In  1867,  Dragendorff  published  his  well- 
known  elaborate  scheme  for  the  separation  of  plant-principles  by  immiscible 
solvents. 


.USE  OF  IMMISCIBLE   SOLVENTS. 


155 


measure  of  chloroform,  99  per  cent,  of  the  whole  substance  will 
pass  into  the  chloroform.  On  separating  this  layer,  and  again 
agitating  the  aqueous  liquid  with  an  equal  quantity  of  chloro- 
form, 99  per  cent,  of  the  remaining  substance  will  be  dissolved, 
thus  making  the  exhaustion  practically  complete.  In  the  case 
of  ether  and  amylic  alcohol,  the  solubility  of  the  solvent  itself 
in  the  aqueous  liquid  is  also  an  important  consideration ;  for,  as 
ether  is  soluble  in  about  ten  times  its  measure  of  water,  on 
agitating  together  equal  measures  of  ether  and  an  aqueous  liquid, 
it  may  be  assumed  that  one-tenth  of  the  ether  will  be  dissolved, 
and  will  remain  in  the  aqueous  liquid  together  with  its  one- 
tenth  share  of  the  alkaloid  or  other  substance  to  be  extracted. 
On  separating  the  ethereal  layer,  and  again  shaking  the  aqueous 
liquid  with  an  equal  measure  of  ether,  it  may  be  considered 
that  nine-tenths  of  the  previously  dissolved  ether  and  its  alkaloid 
will  be  recovered  in  the  immiscible  solvent.  On  the  other  hand, 
the  ethereal  layer  is  not  wholly  free  from  water,  which  may  be 
expected  to  take  up  certain  substances  not  soluble  in  anhydrous 
ether;  but  practically  such  traces  of  impurity  are  removed  on 
agitating  the  ether  with  a  limited  quantity  of  water.  Similar 
considerations  of  solubility  apply  to  treatments  with  chloroform, 
but  with  considerably  less  force  owing  to  its  slight  solubility 
in  water  and  vice-versa;  and  in  the  case  of  petroleum-ether  and 
benzene  they  have  no  practical  bear- 
ing, as  these  solvents  are  almost  abso- 
lutely insoluble  in  aqueous  liquids. 

In  making  a  proximate  analysis  by 
means  of  immiscible  solvents,  much  of 
the  success  in  practice  depends  on  the 
care  and  skill  with  which  the  manipu- 
lation is  conducted.  The  most  con- 
venient apparatus  for  effecting  the 
treatment  consists  of  a  pear-shaped 
(fig.  1)  or  cylindrical  (fig.  2)  glass 
separator,  furnished  with  a  tap  below 
and  a  stopper  at  the  top.  The  tube  be- 
low the  tap  should  be  ground  obliquely 
so  as  to  prevent  loss  of  liquid  by 
imperfect  delivery.     Supposing  that  it 

be  desired  to  effect  the  separation  of  a  substance  from  an  aqueous 
liquid  by  agitation  with  ether,  the  former  is  introduced  into  the 
sei)arator,  of  which  it  should  not  occupy  more  than  one-third,  acid 
or  alkali  added  as  may  be  desired,  and  next  a  volume  of  ether 
about  equal  to  that  of  the  aqueous  liquid.     The  stopper  is  then 


A 


Fi^.  1. 


Fic(.  2. 


156  REPARATION   BY   IMMISCIBLE  SOLVENTS. 

inserted  and  the  whole  thoroughly  shaken  together  for  a  minute 
or  two,  and  then  set  aside.  As  a  rule,  the  contents  will  readily 
separate  into  two  well-defined  layers,  the  lower  of  which  is 
aqueous,  and  the  upper  ethereal.  Sometimes  sei)ai'ation  into  layers 
does  not  occur  readily,  the  liquid  remaining  apparently  homo- 
geneous, forming  an  emulsion,  or  assuming  a  gelatinous  consistency. 
In  such  cases,  separation  may  sometimes  be  induced  by  thoroughly 
cooling  the  contents  of  the  separator.  In  the  case  of  ether, 
the  separation  may  usually  be  effected  by  adding  an  additional 
quantity  of  ether  and  re-agitating,  or,  when  the  employment  of 
a  sufficient  excess  of  ether  is  inconvenient  or  impracticable,  the 
addition  of  a  few  drops  of  alcohol,  followed  by  a  gentle  rotatory 
motion  of  the  liquid,  will  almost  invariably  cause  separation  to 
occur  promptly. 

The  tendency  to  form  an  obstinate  emulsion  is  greatest  when 
the  aqueous  liquid  is  alkaline,  and  is  often  very  troublesome 
when  chloroform,  benzene,  or  petroleum-ether  is  substituted  for 
ether.  In  such  cases,  the  employment  of  a  larger  quantity  of 
the  solvent  sometimes  causes  separation,  but,  when  admissible, 
a  better  plan  is  the  addition  of  ether.  This  answers  very 
successfully  for  the  isolation  of  strychnine,  Avhich  is  nearly 
insoluble  in  unmixed  ether,  but  readily  soluble  in  a  mix- 
ture of  equal  measures  of  ether  and  chloroform.  This  solvent 
is  heavier  than  water,  and  is  capable  of  very  extensive  appli- 
cation. 

Separation  having  taken  place,  the  aqueous  layer  should  be 
run  ofi"  by  the  tap  into  another  separator,  where  it  can  again 
be  agitated  with  ether  to  insure  the  complete  removal  of  the 
body  to  be  dissolved  therein.  The  ethereal  liquid  remaining  in 
the  first  separator  should  be  shaken  with  a  fresh  quantity  of 
alkalised  or  acidulated  water,  which  is  then  tapped  ofi"  as  before, 
and  the  remaining  traces  removed  by  treating  the  ether  with  a 
little  pure  water.  This  having  in  turn  been  run  ofif  to  the 
last  drop,  the  ethereal  solution  can  next  be  removed  by  the  tap, 
but  a  preferable  plan  is  to  pour  it  off  from  the  mouth  of  the 
separator,  taking  care  to  avoid  the  draining  of  any  drops  of 
aqueous  liquid  from  the  sides  of  the  glass. 

When  amylic  alcohol,  benzene,  or  petroleum  ether  is  employed, 
the  manipulation  is  the  same  as  that  just  described ;  but  when 
chloroform  is  used,  or  a  mixture  containing  a  considerable  pro- 
portion of  that  solvent,  the  aqueous  liquid  forms  the  upper 
stratum,  and  the  chloroformic  solution  can  at  once  be  removed 
by  the  tap. 

When  the  volume  of  fluid  treated  with  the  immiscible  solvent 


SEPARATION  BY   IMMISCIBLfc  SOLVENTS. 


157 


f 


i 


is  very  small,  the  syringe  pipette  shown  in 

veniently  substituted  for   a   tapped  separator. 

structed   by   drawing   out   a    test-tube,    so   as 

prolongation,   the    orifice    of    which 

not  to  disturb  the  liquid  in 

which    it    is    immersed.      A 

narrow    test-tube    fashioned 

into  a  handle  at  the  upper 

part   serves    as    a    piston,   a 

short  length  of  india-rubber 

tubing  uniting  it  to  the  outer 

tube,  while  allowing  of  easy 

movement  both  in  a  vertical 

and  a  horizontal  direction. 

Another  convenient  form 
of  separator,  devised  by  W. 
C  h  a  1 1  a  w  a  y,  is  shown  in 
fig.  4.  It  is  practically  a 
small  wash  -  bottle  fitting, 
which  is  adjusted  to  the 
tube  or  cylinder  containing 
the  layers  of  liquid  it  is 
desired    to   separate.      It  is 


3g.  3  may  be  con- 
It  is  readily  con- 
to    form    a    narrow 
should  be   turned   up  so   as 


so   arranged    that    the    exit- 


I 


Fig.  3. 


tube  (B)  can  be  adjusted  in 

height  by  sliding  it  through 

the  india-rubber   collar  C,  so  as  to  bring  the  tumed-up  end  just 

above  the  junction  of  the  two  layers.      On  then  blowing  through 

the  side-tube  (A),  the  upper  stratum  is  forced  up  the  inner  tube, 

and  can  be  removed,  almost  to  the  last  drop,  without  disturbing 

the  lower  layer. 

The  following  table  shows  the  behaviour  of  various  classes  of 
organic  substances  when  shaken  in  acidulated  or  alkalised  solution 
with  immiscible  solvents,  such  as  ether,  chloroform,  amylic  alcohol, 
benzene,  and  petroleum  ether.  It  must  not  be  supposed,  how- 
ever, that  the  immiscible  solvents  can  be  employed  indifferently, 
as  some  of  the  bodies  are  readily  removed  by  certain  solvents, 
but  are  unaffected  by  others  owing  to  their  limited  solubility 
therein.  This  is  especially  the  case  with  the  alkaloids  and 
glucosides,  and  hence  the  table  must  merely  be  regarded  as 
showing  their  general  tendency,  their  special  behaviour  with 
the  different  solvents  being  deferred  for  fuller  description  later 
on. 


158 


SEPARATION   BY   IMMISCIBLE   SOLVENTS. 


Table  showing  the  behaviour  of  Organic  Substances  with 
Immiscible  Solvents. 


On  agitating  the  substance  with  water,  acidulated  with  sulphuric  acid,  and  a  suitable 
solvent  immiscible  therewith  (such  as  ether,  chloroform,  amylic  alcohol,  benzene, 
or  petroleum  ether),  the  following  distribution  will  occur : — 


The  Immiscible  Later  will  contain 
hydrocarbons,  oils,  various  acids,  resins, 
colouring  matters,  phenols,  glucosides, 
&c.,  which  may  be  fui'ther  separated  by 
agitating  the  liquid  with  water  con- 
taining caustic  soda,  when  there  will  be 
obtained : — 


In  the  Immiscible 
Layer— 

Solid  Hydrocarbons  ; 
as  paraffin,  naph- 
thalene, anthra- 
cene. 

Liquid  Hydrocar- 
bons ;  as  petrole  um 
products,rosin-oil, 
benzene. 

Essential  Oils ;  as 
turpentine. 

Nitro  -  compounds; 
as  nitrobenzene. 

Ethers  and  their 
Allies;  as  ether, 
chloroform,  ethe- 
real salts,  nitro- 
glycerin. 

Fixed  Oils,  Fats,  and 
Waxes. 

Neutral  Resins  and 
Colouring  Matters. 

Chlorophyll. 

Camphors;  as  laurel- 
camphor,  borneol, 
raenthoL 

Alcohols  insoluble  or 
nearly  insoluble  in 
water ;  as  amyl 
and  cetyl  alcohols, 
cholesterin. 

Certain  Glucosides, 
<bc.  ;  as  saponin, 
digi  talin,  santonin. 

Certain  Weak  Alka- 
loids; as  caffeine, 
colchicine,  naroo- 
tine,  piperine,  theo- 
bromine. 


In  the  Alkaline 
Aqueous  Liquid— 

Fatty  Acids;  as 
stearic,  oleic, 

valeric. 

Various  other  Acids ; 
as  benzoic,  sali- 
cylic, phthalic, 
meconic. 

Acid  Dyes  and  Col- 
ouring Matters  ; 
as  picric  and  chry- 
sophanic  acids, 
alizarin,  aurin, 
bilirubin. 

Acid  Resins ;  as 
colophony. 

Phenoloids;  as  car- 
bolic and  cresylic 
acids,  thymol, 
creosote. 

Certain  Glucosides, 
dkc. ;  as  santonin, 
cantharidin,  picro- 
toxin. 


The  Acidulated  Aqueous  Liquid  will 
contain  carbohydrates,  soluble  alkaloids 
and  acids,  organic  bases,  proteids,  &c., 
which  may  be  further  separated  by  add- 
ing a  moderate  excess  of  soda,  and  again 
shaking  with  a  suitable  immiscible  sol- 
vent, when  there  will  be  obtained  :— 


In  the  Immiscible 
Layer— 

Most  Vegetable  Alka- 
loids ;  as  quinine, 
strychnine,  acoui- 
tine,  atropine, 
nicotine  (cincho- 
nine,  morphine ; 
the  last  two  with 
difficulty). 

Coal-Tar  Bases;  as 
aniline  and  its 
homologues  (ros- 
aniline),  chryso- 
toluidine  (pyri- 
dine), homologues 
of  pyridine. 


In  the  Alkaline 
Aqueous  Liquid— 

Carbohydrates ;  as 
sugars,  gums, 

dextrin. 

Soluble  Alcohols;  as 
methyl  alcohol, 
ethyl  alcohol,  gly- 
cerin. I 

Soluble    Acids;    as 
acetic,  oxalic,  lac-  ! 
tic,  malic,  tartaric,  j 
sulphopheiiic.  I 

Certain  A  Ikaloids  and 
Organic  Bases ;  as 
curarine,  cytisine, 
narceine,  urea, 
glycocine,  sola- 
nine,  and  possibly 
cinchonine,  mor- 
phine ana  pyri- 
dine. 

Certain  Colouring 
Matters ;  as  indigo- 
products. 

Prof  elds  and  their 
Allies;  as  albumin, 
casein,  gelatin. 


The  foregoing  table  merely  exhibits  the  general  behaviour  of 
the  alkaloids  and  other  plant-principles  on  agititing  their  solutions 
with  immiscible  solvents.  G.  Dragendorff,  however,  has  elaborated 
the  following  scheme  for  systematic  treatment  by  immiscible 
solvents.  The  statements  are  made  on  his  authority,  and  in 
some  cases  {e.g.,  the  alleged  removal  of  cinchonine  from  acid 
solutions  by  chloroform)  are  of  questionable  accuracy. 


SEPARATION   BY   DRAGENDORFF  S   METHOD. 


159 


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160  SEPARATION   BY   IMMISCIBLE   SOLVENTS. 

It  is  evident  that  the  method  of  Dragendorff,  set  forth  in  the 
foregoing  table,  effects  some  very  important  differentiations ;  but 
for  many  purposes  the  process  may  be  simplified  with  advantage. 
Thus,  for  instance,  if  the  directions  of  Dragendorff  be  adhered  to, 
the  aqueous  solution  will  be  treated  at  least  seven  times  (and 
possibly  twice  as  many)  with  immiscible  solvents  before  the 
extraction  of  morphine  with  amylic  alcohol  is  attempted.  As 
morphine  is  not  wholly  insoluble  in  the  solvents  previously  used, 
small  quantities,  such  as  are  generally  met  with  in  toxicological 
inquiries,  are  liable  to  escape  detection.  Again,  agitation  of  the 
acidulated  liquid  with  petroleum-ether  removes  but  few  active 
principles,  though  it  is  often  useful  for  purifying  the  liquid  from 
colouring  matters,  traces  of  resins,  and  fatty  acids  precipitated  on 
acidulating,  &c.  The  subsequent  treatments  with  benzene  may 
often  be  omitted,  as  the  bodies  thereby  extracted  are  also  dissolved 
by  chloroform.  They  consist  of  glucosides  and  other  neutral 
and  feebly  acid  principles,  with  a  few  alkaloids  of  feeble  basic 
character.  The  treatment  with  petroleum-ether  in  ammoniacal 
solution  is  chiefly  of  service  for  the  isolation  of  the  volatile  bases 
(conine,  nicotine,  sparteine,  &c.),  and  in  their  absence  may  often 
be  advantageously  omitted.  In  fact,  the  three  extractions  in 
ammoniacal  solution  by  petroleum-ether,  benzene,  and  chloroform 
may  in  many  cases  be  replaced  by  treatment  with  chloroform 
alone,  or  a  mixture  of  ether  and  chloroform,  which  last  menstruum 
possesses  the  great  advantage  of  separating  readily  from  alkaline 
liquids. 

The  alkaloids  and  other  principles  having  been  separated  into 
groups  by  Dragendorff's  method,  the  various  solutions  may  be 
carefully  evaporated  and  the  residues  examined  for  the  substances 
supposed  to  be  present.  The  special  tests  suitable  for  this  purpose 
are  described  in  the  sequel. 

A  valuable  method  of  extracting  alkaloids  is  that  of  C  1  a  u  s, 
who  employed  it  especially  for  the  estimation  of  caffeine  in  tea, 
and  of  quinine  in  bark,  but  it  is  capable  of  many  other  applica- 
tions. In  assaying  tea,  the  powdered  leaves  are  dried  and 
extracted  with  ether,  the  solvent  dissolved  off,  and  the  residue 
extracted  with  sulphuric  acid.  The  acid  liquid  is  filtered,  mixed 
with  excess  of  ignited  magnesia,  evaporated  to  dryness  at  100°, 
and  the  residue  pulverised  and  extracted  with  boiling  ether.  For 
the  extraction  of  quinine,  the  powdered  bark  is  exhausted  by 
water  acidulated  with  sulphuric  acid,  the  solution  evaporated  with 
excess  of  magnesia,  and  the  dry  residue  exhausted  with  ether. 

A.  Loesch  {Year-Book  Pharm.,  1880,  page  60)  treats  the 
«^rude  and  concentrated   alkaloidal   solution   obtained  by  suitable 


EXTRACTION   OF   ALKALOIDS. 


161 


means  with  three  measures  of  a  cold  saturated  solution  of  alum, 
and  then  adds  a  slight  excess  of  ammonia.  The  liquid  containiiig 
the  precipitate  is  evaporated  to  dryness  at  100°,  and  the  powdered 
residue  exhausted  with  a  suitable  solvent.  On  evaporating  the 
solution,  the  alkaloid  is  obtained  in  colourless  ash-free  crystals. 
Loesch  quotes  the  following  results,  as  compared  with  those 
yielded  by  Glaus'  magnesia  method,  and  titration  by  Mayer's 
solution  (page  140): — 


Material  Employed. 


Percentage  of  Alkaloid  Extracted. 


Glaus. 


Mayer.  Loesch. 


Cinchona  bark  (yellow), 
Cinchona  bark  (red) , 

Cinchona  bark  (brown), 

Hyoscyamus  leaves, 
Hyoscyamns  seeds,  . 
Belladonna  leaves,  . 
Belladonna  roots, 
Ipecacuanha  root, 
Aconite  leaves, 


quinine,    . 
cinchonidine, 
quinine,    . 
cinchonidine, 
quinine,    . 
cinchonidine, 


3-175 
0-250 
1195 
0-500 
0-950 
2-975 
0145 
0-225 
0-197 
0-325 
0-800 
0-395 


2-570 
0175 
1-005 
0-395 
0-800 
2-300 
0-074 
0-100 
0-090 
0-225 
0-476 
0-220 


3-250 
0-285 
1-235 
0-525 
0-975 
3  075 
0-175 
0-285 
0-236 
0-376 
0-875 
0-425 


J.  U.  Lloyd  (Pharm.  Jour.,  [3],  xxi.  1144)  recommends 
for  the  assay  of  alkaloidal  extracts  the  addition  of  ferric  chloride 
solution,  and  then  sufficient  solid  sodium  bicarbonate  to  convert 
the  whole  into  a  paste.  This  is  treated  in  a  porcelain  mortar  with 
chloroform,  which  is  poured  off  and  the  treatment  twice  repeated. 
The  alkaloid  is  then  shaken  out  from  its  chloroform  solution  with 
dilute  acid,  the  latter  liquid  agitated  with  ether  to  remove  chloro- 
phyll, &c.,  and  the  alkaloid  again  liberated  and  extracted  by  a 
suitable  solvent. 

If  a  volatile  alkaloid  be  present  it  will  generally  be  evident 
by  its  odour,  at  whatever  point  of  the  operation  it  is  liberated 
from  its  combination  by  an  alkali.  Should  its  presence  be 
thus  detected  or  suspected,  it  may  be  conveniently  isolated  by 
adding  excess  of  lime  or  baryta,  and  distilling  the  liquid.  The 
alkaloid  can  be  fixed  in  the  distillate  by  adding  a  slight  excess 
of  hydrochloric  acid,  and  after  concentrating  the  liquid  to  a  small 
bulk  may  be  liberated  by  adding  a  large  excess  of  caustic  alkali, 
and  extracted  by  agitation  with  ether  (compare  page  170). 

The  alkaloids  having  been  obtained  in  a  state  of  approximate 
purity  by  one  of  the  foregoing  methods,  they  may  be  further 
treated  according  to  one  of  the  following  principles,  which  may 
be  applied  in  many  cases  at  an  early  stage  of  the  process. 

VOL.  III.  PART  II.  L 


162  PURIFICATION   OF   ALKALOIDS. 

a.  Fatty  and  resinous  matters  and  chlorophyll  may  be  removed 
by  agitating  the  acidulated  solution  of  the  alkaloid  with  petroleum 
spirit  or  ether.     (Piperine  and  some  glucosides  are  also  extracted.) 

h.  Colouring  matters  may  be  removed  by  agitating  the  solution 
with  a  small  quantity  of  animal  charcoal/  but  this  agent  must  be 
used  very  sparingly,  or  the  alkaloid  may  be  wholly  removed  from 
solution.  The  alkaloid  thus  taken  up  may  be  recovered  by  boil- 
ing the  charcoal  with  alcohol.  The  absorption  of  alkaloids  by 
charcoal  has  been  employed  for  their  removal  from  beer  and 
similar  liquids. 

c.  Many  colouring  matters,  and  tannic  and  various  other  organic 
acids,  may  be  removed  by  treating  the  neutral  solution  with  lead 
acetate,  and  filtering. 

d.  From  sugars,  gums,  salts,  and  extractive  matters  generally, 
the  great  majority  of  the  alkaloids  can  be  separated  by  adding 
ammonia,  and  agitating  the  solution  with  chloroform  or  a  mixture 
of  chloroform  and  ether.  On  separating  the  chloroform  from  the 
aqueous  liquid,  which  retains  the  sugar,  gum  and  salts,  and 
agitating  it  with  dilute  sulphuric  acid,  the  alkaloid  passes  into 
the  acid  liquid,  while  colouring  matters,  fats,  resins,  &c.,  remain 
in  the  chloroform. 

e.  The  alkaloid  may  be  precipitated  with  iodised  potassium 
iodide,  Mayer's  reagent,  auric  chloride,  or  platinic  chloride,  the 
precipitate  being  purified  by  recrystallisation  from  water,  alcohol, 
or  other  suitable  solvent,  and  recovered  by  appropriate  means. 

By  a  judicious  application  of  the  above  principles  it  is  generally 
an  easy  matter  to  isolate  alkaloids  in  a  nearly  pure  condition,  or 
at  any  rate  in  such  a  state  as  to  allow  of  the  special  tests 
being  successfully  applied.  H.  B.  P  a  r  s  o  n  s'  systematic  scheme 
for  the  proximate  analysis  of  plants  detailed  in  Yol.  I.  page  365 
et  seq.  will  also  be  of  service  in  the  isolation  of  alkaloids. 

A  good  example  of  the  separation  of  alkaloids  from  woody 
fibre  and  tannin  matters  is  furnished  by  the  processes  for  the 
assay  of  cinchona  barks;  the  separation  of  alkaloids  from 
resinous,  gummy,  and  colouring  matters  is  exemplified  in  the 
methods  for  the  assay  of  opium;  while  the  isolation  of 
strychnine  in  toxicological  investigations  is  a  good  illustration 
of  the  methods  employed  for  the  separation  of  alkaloids  from 
albuminous,  starchy,  and  fatty  matters.  The  last  method  is  of 
tolerably  general  applicability  in  toxicological  investiga- 
tions, provided  that  it  be  remembered  that  (1)  many  alkaloids 
are    far   less    stable    than    strychnine,   and  hence    are    apt  to  be 

1  Made  by  boiling  bone-charcoal  with  hydrochloric  acid,  filtering,  and 
thoroughly  washing  the  insoluble  residue  of  carbon. 


CONSTITUTION   OF   ALKALOIDS.  163 

destroyed  if  the  solutions  are  evaporated  at  too  high  a  tempera- 
ture (compare  aconitine) ;  (2)  that  certain  alkaloids  are  extracted 
by  chloroform  and  amylic  alcohol  even  from  their  acidulated  solu- 
tions ;  (3)  that  curarine,  cytisine,  morphine,  and  solanine  are  nearly 
or  quite  insoluble  in  ether  or  chloroform,  and  hence  cannot  be 
certainly  extracted  by  agitating  their  alkaline  solutions  with  either 
of  these  solvents;  (4)  that,  whenever  possible,  the  chemical  tests 
for  the  isolated  alkaloids  should  be  supplemented  by  physiological 
tests ;  and  (5)  that,  during  the  process  of  putrefaction,  certain 
cadaveric  alkaloids  ("  ptomaines  ")  are  liable  to  be  formed  which 
simulate  some  of  the  reactions  of  the  vegetable  bases,  but  are 
distinguishable  from  them  by  careful  examination. 


CONSTITUTION  AND  SYNTHESIS  OF  ALKA- 
LOIDS.^ 

Some  of  the  alkaloids  of  widely  different  properties  present  a 
curious  analogy  in  their  formulas.  This  resemblance  in  empirical 
composition  is  merely  accidental,  as  is  proved  in  many  cases  by 
the  products  of  decomposition.  The  following  are  some  of  the 
most  striking  cases  of  the  kind : — 

r  Atropine,  C17H23NO3  (  Colchicine,       CoaHggNOg 

(  Cocaine,  C^^HgiNO^  \  Narcotine,        CggHggliOy 

J  Morphine,         CiyHjgNOg  f  Quinine,  C.^qK^^'N^O,^ 


Piperine,  Ci^H^gNOg  (  Strychnine,      C21H21N2O2 

(  PseudaconitinCjCggH^gl^Oi,  J  Picraconitine,  CgiH^gNOj^ 

\  Veratrine,  C37H53NO11  \  Cevadine,         CggH^gNOg 


The  foregoing  coincidences  have  little  theoretical  value,  as  no 
real  insight  into  the  constitution  of  the  alkaloids  can  be  obtained 
by  a  consideration  of  mere  empirical  formulae. 

Some  of  the  most  important  advances  in  the  synthetical  pro- 
duction of  alkaloids  have  been  due  to  a  study  of  the  products 
obtained  by  hydrogenating  pyridine  and  its  allies,  assisted  by 
a  better  recognition  of  the  relationship  of  these  bases  to  each 
other,  and  to  benzene  and  other  hydrocarbons.  Thus,  the  bases 
pyridine,  quinoline,  and  acridine  form  a  series  related  to  each 
other  exactly  in  the  same  way  as  the  hydrocarbons  benzene, 
naphthalene,  and  anthracene  are  related  (page  39).     The  stability 

^  Much  of  the  information  contained  in  the  test  is  derived  from  a  lecture 
by  S.  P.  Sad  tier  {Pharm.  Jour.,  [3],  xx.  544),  and  from  the  address  of 
A.  B.  Prescott  to  the  Chemical  Section  of  the  American  Association  for 
the  Advancement  of  Science  {Pharm.  Jour.,  [3],  xviii.  520,  541). 


164  PYRIDINE  DERIVATIVES. 

and  the  behaviour  towards  reagents  of  the  corresponding  derivatives 
of  benzene  and  pyridine  are  exactly  analogous,  as  also  is  their 
behaviour  on  reduction.  Just  as  from  benzene  hexahydrobenzene 
can  be  obtained,  so  from  pyridine  hexahydropyridine  may  be 
prepared,  but  far  more  readily.  Similarly  from  naphthalene  and 
quinoline,  tetrahydro-additive-products  are  obtainable,  while  from 
anthracene  and  acridine,  respectively,  dihydro-anthracene  and 
dihydro-acridine  (page  125)  have  been  obtained. 

Of  these  hydro-addition- products,  one  of  the  best-studied  is 
hexahydropyridine,  CgH^iN,  which  is  identical  with  the 
volatile  base  piperidine,  obtainable  from  piperine,  CjgHjgNOg,  the 
alkaloid  of  pepper,  by  distillation  with  alkali,  by  the  action  of 
reducing  agents  on  p  y  r  i  d  i  n  e,  C;;!!^^,  or  by  heating  the  hydro- 
chloride of  pentamethylen e-d i a m i n e,  C5Hio(NH2)2  (page 
106). 

Another  natural  plant-base  which  has  been  prepared  synthetically, 
and  the  nature  and  derivation  of  which  are  clearly  understood, 
is  Conine,  CgH^yN,  the  volatile  poisonous  alkaloid  of  hemlock. 
Conine  is  the  dextro-rotatory  variety  of  a-normal-propyl- 
piperidine,  05X1^0(03117)^".  To  prepare  it  synthetically,  pyri- 
dine is  first  converted  into  a-allyl-piperidine,  05H4N(03H5), 
which  is  then  reduced  in  alcoholic  solution  by  means  of  sodium. 
In  this  reaction,  the  chief  product  is  the  optically  inactive  a-nor- 
mal-propyl-piperidine,  which  is  separated  by  crystallisa- 
tion of  the  tartrate  into  ordinary  conine  (dextro-conine),  and  a 
Isevo-rotatory  conine  which  closely  resembles  the  other  modifica- 
tion.^ 

The  optically  inactive  conine  can  also  be  prepared  from  cony- 
r  i  n  e,  or  a-normal  -propyl-piperidine,  by  treatment  with  hydriodic 
acid,  or  from  conhydrine^  OigH^^NO,  an  oxy-derivative  occurring 
with  conine  in  hemlock.  A.  W.  Hofmann  has  described  three 
isomeric  bases,  called  a-,  p-,  and  y-coniceine,  having  the  formula 
CgHjgN,  and  hence  differing  from  conine  by  Hg.  These  bases 
have  a  mousy  smell  like  conine,  and  the  a  and  y  modifications 
are  more  powerful  poisons  than  conine  itself  (see  page  174). 

Nicotine,  OioHj^Ng,  the  volatile  alkaloid  of  tobacco,  is  another 
base  related  to  pyridine,  and  the  synthesis  of  which  has  been  at 
least  partially  effected.  Thus  the  two  known  dipyridyls, 
C^oHgNg,  are  the  para-  and  me^a-modifications.  On  reduction, 
these  yield  the  corresponding  hexahydro-dipyridyls, 
^io-^8(H6)-^2'  which  are  bases  called  respectively  isonicotine 

^  These  two  bases  bear  the  same  relation  to  each  other,  and  to  the  inactive 
modification  that  dextro-  and  Isevo-tartaric  acids  bear  to  racemic  acid. 
Exactly  analogous  ethyl-piperidines  have  been  prepared. 


PYRIDINE-CARBOXYLIC   ACIDS.  165 

and  nicotidine,  isomeric  with  nicotine.  On  treatment  with 
oxidising  agents  nicotine  yields  nicotinic  or  |8-pyridine- 
carboxylic  acid,  CgH^N.COOH,^  a  reaction  which  shows  the 
close  relationship  of  nicotine  to  the  homologues  of  pyridine. 

Atropine,  C17H23NO3,  is  another  plant-base  of  which  the 
relationship  to  pyridine  has  been  very  clearly  established.  Thus 
when  boiled  with  alkalies  atropine  is  hydrolysed  into  t  r  O' 
pine,  CgHjgNO,  and  tropic  acid,  CgHj^Og ;  while  hyoscine, 
base  isomeric  with  atropine,  is  similarly  split  up  into  tropic 
acid  and  pseudotropine.  Tropine  has  the  constitution 
of  a  hydroxyethyl-methyl-tetrahydropyridine, 
C6H7(C2H^OH)(CH3)N.  On  boiling  with  acids  it  loses  the 
elements  of  water  and  is  converted  into  tropidine,  a  liqiud  base 
with  a  conine-like  odour,  and  has  been  synthesised  by  Ladenburg 
by  introducing  a  methyl  and  hydroxyethyl  atom  into  tetrahydro- 
pyridine.  Tropic  acid  and  tropine  reunite  to  form  atropine  when 
their  solutions  in  dilute  hydrochloric  acid  are  mixed  and  evapor- 
ated. By  substituting  other  aromatic  acids  for  tropic  acid  a  great 
variety  of  bodies  can  be  obtained,  which  are  generically  termed 
tropeines,  and  one  of  which,  the  mandelic  acid  derivative  or 
homatropine,  has  proved  physiologically  important. 

The  pyridine-carhoxylic  acids  (page  110),  and  their  analogues 
and  derivatives,  have  shown  some  unexpected  relationships  to  the 
natural  plant-bases.  The  /3-pyridine-carboxylic  acid 
(nicotinic  acid)  results  from  the  oxidation  of  nicotine  and  pilo- 
carpine. Cinchomeronic  acid  (a-pyridine-dicarboxylic  acid) 
is  produced  by  the  oxidation  of  cinchonine,  cinchonidine,  and 
quinine.  One  of  the  pyridine-tricarboxylic  acids  is 
produced  by  the  oxidation  of  the  cinchona-bases  and  papaverine 
with  permanganate,  while  a  second  results  from  the  oxidation  of 
berberine  by  nitric  acid.  The  pyridine-carboxylic  acids  also  furnish 
additive-products  analogous  to  the  betaine  of  beet-juice,  and  closely 
related  to  the  natural  alkaloids.  The  synthetically  produced  betaine 
of  nicotinic  or  /3-pyridine-carboxylic  acid  has  been  shown  to  be 
identical  with  the  alkaloid  of  Trigonella  foenugr cecum,  while  the 
betaine  of  cinchmoeronic  acid  is  identical  with  apophyllic 
acid,  obtained  by  the  oxidation  of  cotarnine  (see  narcotine). 

The  pyridyl-residue,  C^H^N,  is  capable  of  replacing  an 
atom  of  hydrogen  in  the  molecule  of  certain  acids,  the  compounds 
having  the  same  relation  to  the  salts  of  pyridine  that  {e.g.)  aniline 
acetate  has  to  acetanilide.     Pilocarpidine,  which  occurs  with  pilo- 

^  The  same  pyridine-carboxylic  acid  may  be  obtaiued  by  the  action  of 
ammonia  on  c o u m a  11  n i c  acid,  produced  by  the  action  of  sulphuric  acid 
on  muUc  acid. 


166  CONSTITUTION  OF  ALKALOIDS. 

(jarpinQ  in  japorandi  leaves,  is  a  ^  -  p  y  r  i  d  i  ne  -  a  -  d  i  m  e  t  h  y  !-'• 
amidopropionic  acid,  having  probably  the  constitution  :— ^ 
N(CH3)2.C(CH3)C5H4N.COOH.  It  has  been  prepared  syntheti- 
cally, and  from  it,  by  the  action  of  methyl  iodide  and  caustic  alkali, 
followed  by  silver  permanganate,  pilocarpine  itself  has  been  ob- 
tained, and  inay  be  regarded  as  having  the  following  constitution  : — 
C,H,N.C(CH3)N(CH3)3 

CO-0 

The  action  of  ammonia  upon  certain  acids  found  in  the  vegetable 
kingdom  has  been  found  to  produce  bodies  related  to  pyridine.. 
Thus  comanic  acid,  G^fi^,  derived  from  meconic  acid,  is 
changed  by  ammonia  into  an  oxypicolinic  acid,  while  c  o  m  e  n  i  c 
acid,  CgH^Og,  from  the  same  source,  yields  a  dioxypicolinic  acid, 
comenamic  acid,  CgH5N04.  Similarly  chelidonic  acid, 
CiyH^Og,  which  accompanies  the  alkaloids  chelidonine  and  san- 
guinarine  in  Chelidonium  majus,  yields  an  oxypyridine- 
carboxylic  acid  on  treatment  with  ammonia. 

Colchicine  is  another  alkaloid  the  constitution  of  which  is  fairly 
well  known.  From  its  reactions  and  the  products  of  its  decomposi- 
tion, it  is  evidently  the  methyl-ester  of  ace ty l-trimethyl- 
c  o  1  ch  i  c  i  n  i  c  acid,  (O.CH3)3.Ci5H9(NH.C2H30).CO.OCH3. 

Ecgonine  has  the  constitution  of  a  methyltetrahydropyridyl- 
hydroxypropionic  acid,  C5HgMeN.CH(OH).CH2.COOH.  It  results, 
together  with  methyl  alcohol  and  benzoic  acid,  from  the  decora- 
position  of  cocaine  by  alkalies.  Cocaine  may  be  made  synthetically 
by  heating  ecgonine  with  benzoic  anhydride  and  methyl  iodide, 
and  has  the  following  constitution  : — 

C5He(CH3)KCH(O.C7H50).CH2.COO(CH3). 

A  series  of  analogous  artificial  alkaloids  have  been  prepared  by 
combining  ecgonine  with  other  acids  besides  benzoic. 

The  constitution  of  the  aconite  bases  is  partially  known,  for 
they  split  under  the  influence  of  hydrolysing  agents  into  simpler 
bases  and  acids  of  the  aromatic  series  ;  aconitine,  picraconitine, 
and  japaconitine  yielding  benzoic  acid,  CgHg.COOH,  while 
pseudaconitine  gives  veratric  or  diniethy  1-pro to ca te- 
ch uic  acid,  CeH3(OCH3)2.COOH.  The  pseudaconine, 
CgyH^jNOg,  simultaneously  produced  in  the  last  case,  forms  a  dia- 
cetyl-derivative,  and  hence  probably  contains  two  hydroxyl  groups. 

Veratric  acid  is  also  produced,  together  with  v  e  r  i  n  e,  C28H45NO8, 
by  the  saponification  of  veratrine,  while  the  accompanying  base, 
cevadine,  CggH^gNOg,  is  converted  on  hydrolysis  into  c  e  v  i  n  e, 
C27H43NO8,  and  m  e  t  h  y  1-c  r  0 1 0  n  i  c  acid,  C3H4(CH3).GOOH. ; 


CONSTITUTION  OF  OPIt^M  BASES.  167 

Sinapine,  CigHggNO^,  an  alkaloid  the  thiocyanate  of  which 
exists  in  white  mustard  seed,  is  split  by  boiling  with  baryta- 
water  into  sinapic  acid,  CiiH.^Jd^,  and  choline,  C^gHjgNOg, 
a  base  which  is  contained  in  bile  and  other  animal  products, 
as  well  as  in  hops  and  certain  other  plants.  Choline  has  itself 
been  obtained  synthetically,  and  has  the  constitution  of  a 
hydroxy  e  thy  1-trimethyl-ammonxum  hydroxide, 
(C,H,OHXCH3)3N.OH. 

Theobromine,  C^'H.^^CB.^^'NJ^^,  the  alkaloid  of  cocoa,  and 
caffeine,  C5H(CH3)3N^02,  the  alkaloid  of  tea  and  coffee,  are 
respectively  the  dimethyl  and  trimethyl  derivatives 
of  xanthine,  CgH^N^Og,  a  body  occasionally  occurring  in  urinary 
calculi  and  produced  by  the  action  of  nitrous  acid  on  guanine, 
C5H5N5O  (contained  in  guano),  or  by  treating  uric  acid, 
CgH^N^Og,  with  sodium  amalgam. 

Lupinine,  an  alkaloid  found  in  seeds  of  Lupinvs  luteus,  has  the 
formula  C2iH38N2(OH)2.  Arginine,  CoH.^^'^fi^,  from  the  same 
source  (page  178)  yields  urea  when  boiled  with  baryta  water. 

The  manner  in  which  the  oxygen  of  the  natural  alkaloids  exists 
is  in  most  cases  but  little  understood.  Morphine,  Cj^H^gNOg, 
appears,  however,  to  have  a  phenolic  character,  and  contains  two 
hydroxyl  atoms  replaceable  by  acetyl  or  benzoyl.  Codeine  is  a 
substituted  morphine  in  which  one  of  the  hydroxyl  atoms  is 
replaced  by  methoxyl,  OCH3,  and  has  been  obtained  syntheti- 
cally by  heating  morphine  with  methyl  iodide.  By  similar  means 
the  second  hydroxyl  atom  can  be  replaced  by  methoxyl  with 
formation  of  methocodeine.  Thehaine  differs  from  methocodeine 
by  two  atoms  of  hydrogen,  thus  : — 

Morphine,    ....  CiyH^^NO  j  ^^ 

Codeine,       ....  C,,H,,NO  |  ^J^j^^^ 

MethocodeiHB,       .         .         .  C17H17NO  |  ^^^^s) 

Thebaine,      ....  CiyH^gNO  |  ^(^^s) 

When    distilled    with    zinc-dust,    morphine    yields    phenanthrene 
Ci^H^Q,  and  pyridine,  Cr,H5l!f. 

Narcotine,  C22H27NO7,  is  saponified  under  certain  conditions 
with  formation  of  meconin,  CiqHiq04,  and  cotarnine, 
C12H13NO3;  and  the  latter  body  when  treated  with  bromine 
yields  dibrompyridine,  C5H3Br2K  Cotarnine  probably  con- 
tains its  oxygen  in  the  forms  of  CO.OCH3  and  OCHg.     On  oxida- 


168  CONSTITUTION   OF  CINCHONA   BASES. 

tion  it  yields  apophyllic  acid,  a  body  which,  when  heated 
under  pressure  with  hydrochloric  acid,  behaves  like  the  methyl- 
ester  of  cinchomeronic  acid  : — 

CAN  {  CO;OH  ^^^+HC1  =  CH3C1  +  C,H3N  {  CJ-OH 

Apophyllic  acid.  Methyl  chloride.  Cinchomeronic  acid. 

Papaverine,  CgoHgiNO^,  is  another  opium  base,  the  constitution 
of  which  is  probably  :— (OCH3)2C9H4N.CH2.C6H3(OCH3)2. 

Bvucine,  CggHggNgO^,  when  fused  with  caustic  potash  yields 
homologues  of  pyridine,  while  strychnine,  CgiHggNgOg,  yields 
q  u  i  n  0 1  i  n  e  and  indole,  CgH^N. 

Quinine,  C2oH24N'20,  when  fused  with  caustic  potash  yields 
methoxy-quinoline,  C9Hg(O.CH3)N.  When  subjected  to 
careful  oxidation  with  permanganate  or  weak  chromic  acid  mixture 
it  at  first  yields  formic  acid,  CH2O2,  and  a  weak  base  called 
quitenine,  C19H22N2O4.  Further  oxidation  produces  three 
bases,  to  which  Skraup  attributes  the  formulae  CigH^gNOg, 
C9H17NO2,  and  C9H7NO.  The  first  of  these  has  been  little 
studied,  the  second  has  been  named  cincholeupone,  CgH^^NO^, 
and  the  third  appears  to  be  identical  with  kynurine,  a  base 
obtained  by  heating  kynurenic  acid,  a  constituent  of  dog's  urine. 
Besides  these  bases  there  are  produced  cincholeuponic 
acid,  C8Hi3N04;i  quininic  acid,  C9H5(O.CH3)KCOOH ; 
then  a  pyridine-tricarboxylic  acid,  C5H2N(CO.OH)3 ; 
and  finally  the  pyridine-dicarboxylic  acid  known  as  cincho- 
meronic acid,  C5H3N(CO.OH)2.  Quinidine  and  quinicine 
yield  the  same  products  as  quinine.  Ginchonine,  C^^^^^^O, 
when  similarly  subjected  to  limited  oxidation,  yields  formic  acid 
and  cinchotenine,  C18H20N2O3,  as  first  products ;  the  latter 
by  further  treatment  yields  cincholeupone,  C9HJ7NO2,  and  this 
oxidises  to  cinchoninic  acid,  C10H7NO2,  and  cincho- 
leuponic acid,  CgHjgNO^;  the  final  products  being  cin- 
chonic  acid,  CgH^N.COOH  (which  is  a  pyridine-carboxylic 
acid),  and  cinchomeronic  acid  (see  above).  Ginchonidine 
and  cinchonicine  appear  to  yield  the  same  products. 

The  conclusion  derivable  from  the  researches  on  the  constitution 
of  the  cinchona  bases  is  that  both  quinine  and  cinchonine  are 
derivatives  of  a  hydro- diquinoline,  of  which  probably  only  one  side 
is  hydrogenated.  The  same  unreduced  quinoline-residue  is  common 
to   both  alkaloids,  with  the  diflference  that,  while   in  cinchonine 

^  Cincholeuponic  acid  probably  has  the  constitution  ofamethyl-piperi- 
dine-dicarboxylic  acid: — 

HV  /  -CHg  CHg.CHg.  \ 

^^  ^  .C(CH3)(C00H).CH(C00H).  / 


ISOMERS  OF  QUININE.  169 

the  residue  is  quinoline  itself,  in  quinine  it  is  a  m e t h o x y- 
q  u  i  n  0 1  i  n  e.    The  following  formulae  illustrate  these  deductions  :— 

Quinoline,       .  .  CgH^N 

Hydroxyquinoline,  .  C9Hg(0H)N 

Tetrahydroquinoline,  CgHjoN.H 

Diquinoline,  .         .  C9H7N.C9H7N 

Diquinolyline,  C9H10N.C9H10N 

Cinchonine,    .         .  C9H7N.C9Hii(OH)N.CH3 

Quinine,  .         .  C9H6(O.CH3)N.C9Hii(OH)N.CH3 

Other  of  the  cinchona  bases  which  are  known  to  contain 
hydroxyl  groups  are  quinamine,  C2oH23N20(OH),  and  cupreine^ 
C-^^^^.JfiH\.  The  latter  alkaloid,  which  is  found  in  Cuprea 
or  Remijia  bark,  has  recently  been  converted  into  quinine  by 
heating  it  to  100°,  under  pressure,  with  metallic  sodium  and  a 
solution  of  methyl  chloride  in  methyl  alcohol  (Grimaux  and 
Arnold,  Gomp.  Rend.,  cxii.  774). 

Although  the  knowledge  of  the  constitution  of  the  cinchona  bases 
is  not  yet  sufficiently  perfect  to  allow  of  their  formation  from 
pyridine  or  quinoline,  it  is  interesting  to  note  that  two  distinct  basic 
substances  isomeric  with  quinine  have  been  prepared  synthetically. 
One  of  these,  discovered  by  C.  A.  K  0  h  n  {Jour.  Soc.  Chem.  Ind., 
viii.  959),  has  the  constitution  of  an  a-l'-hydro xy -hydro - 
ethylene-quinoline, 

C8H.„(OH)N.C2H,.N.C,HJOH). 

It  was  obtained  by  the  action  of  one  molecule  of  ethylene  di- 
bromide  on  two  molecules  of  a-l'-hydroxyhydroquinoline,  obtained 
by  reducing  hydroxy-quinoline  by  tin  and  hydrochloric  acid.  It  is 
a  weak  base,  forming  small  glittering  prisms  which  melt  at  233°, 
and  are  readily  soluble  in  chloroform  and  benzene,  with  difficulty 
in  hot  alcohol,  and  insoluble  in  water.  It  has  weak  antipyretic 
characters. 

The  other  synthetical  isomer  of  quinine  has  been  prepared  by 
Wallach  and  Otto  {Annalen,  ccliii.  251)  by  the  reaction  of 
/3-naph thy  1  amine  on  pinol  nitroso chloride: — 

C10H7.NH2  +  CioHigO.NOCl  =  HCl  +  C2oH2,N202. 

The  product  is  a  basic  crystalline  substance,  melting  at  194°- 
195°,  insoluble  in  water,  slightly  soluble  in  hot  alcohol,  and 
readily  soluble  in  ether.  The  solutions,  both  of  the  base  and 
its  salts,  are  strongly  fluorescent. 

Besides  the  natural  plant-bases,  a  number  of  bases  have  been 
synthetically  prepared  which   have  every  claim    of   analogy  and 


1^0  VOLATILE  VEGETABLE   ALKALOIDS. 

character  to  be  ranked  with  .  the  alkaloids.  As  instances  of  these 
may  be.  mentioned,  antipyrim,  CiiHj2^2^  (P^g®  32),  thallirie^ 
C10H13NO  (page  120),  siiid  fur/urine,  C[^^^^'Nf>^. 

V.  Meyer  has  suggested  that  the  formation  of  the  bases  and 
other  nitrogenised  constituents  of  plants  may  be  due  in  some 
cases  to  the  action  of  hydroxylamine  on  aldehydic  bodies. 

It  is  a  curious  fact  that  while  the  plant-bases  and  other  natural 
products  not  unfrequently  contain  one  or  more  methyl-groups, 
the  ethyl-radical  is  not  met  with. 


VOLATILE  BASES  OF  VEGETABLE  ORIGIN. 

Certain  plants  contain  bases  which  differ  from  the  ordinary 
vegetable  alkaloids,  in  being  volatile,  liquid  at  ordinary  or  only 
slightly  raised  temperatures,  and  in  containing  no  oxygen.  While 
resembling  each  other  in  the  above  respects,  the  volatile  bases 
present  little  further  resemblance. 

The  volatile  alkaloids  are  not  numerous,  being  limited  to  the 
following  bodies,  and  a  few  others  which  have  been  but  imper- 
fectly investigated. 

a.  Methylamine  and  Trimethylamine,  already  described  (pages 

9,  12). 

b.  Conine  and  the  associated  alkaloids  of  hemlock. 

c.  Lupinine  and  certain  other  alkaloids  of  lupines. 

d.  Nicotine^  the  volatile  alkaloid  of  1 0  b  a  c  c  o. 

e.  Piturine^  the  volatile  alkaloid  of  p  i  t  u  r  i, 
/.   Loheline,  the  alkaloid  of  lobelia. 

g.  Sparteine^  the  alkaloid  contained  in  broom. 
h.  Spigeline,  an  alkaloid  in  Spigelia  Marylandica. 

Piperidine,  a  volatile  alkaloid  said  to  exist  naturally  in  pepper 
as  a  decomposition-product  of  p  i  p  e  r  i  n  e,  has  already  been- 
described  (page  106). 

For  the  estimation  of  volatile  alkaloids  (e.g.,  c  0  n  i  n  e  in  hemlock, 
and  nicotine  in  tobacco),  A.  L  o  e  s  c  h  (Jour.  Amer.  Ghem.  Soc.) 
recommends  that  a  weighed  quantity  of  the  substance  should  be 
boiled  in  water  acidulated  with  hydrochloric  acid,  the  residue 
pressed  and  washed  with  water.  The  solution  and  washings  are 
evaporated  to  one-fourth,  and  then  distilled  with  slaked  lime 
(using  a  good  condenser).  When  the  liquid  passing  over  is  no 
longer  alkaline  to  litmus,  the  distillate  is  exactly  neutralised  with 
sulphuric  acid,  evaporated  to  dryness  at  100°,  and  the  powdered 
residue  exhausted  with  rectified  spirit,  which  leaves  the  ammonium 


ALKALOIDS  OF   HEMLOCK. 


171 


sulphate  undissolved,  while  the  sulphate  of  conine  (and  other 
alkaloids)  pass  into  the  solution.  The  filtered  liquid  is  evaporated 
to  dryness  and  the  residue  skaken  three  times  with  caustic  potash 
solution  and  ether,  the  ethereal  liquid  separated  and  shaken  with 
a  known  volume  of  standard  sulphuric  acid,  the  ether  distilled 
off  or  separated,  and  the  excess  of  sulphuric  acid  determined  by 
titration.  By  this  process,  Loesch  found  5 '2 5  per  cent,  of 
nicotine  in  tobacco  leaves,  and  0"06  per  cent,  of  conine  in  the 
common  hemlock  plant. 

Conine.^     Coniine.     Conia.     Conicine. 
C^Hi^N ;  C,H,„(C3H,)N  ;  or  CH,  {  02^;^^'^'^  }  ^H 

This  base  has  the  constitution  of  an  a-normal-propyl-, 
piperidine  (see  page  1 64). 

Conine  is  the  characteristic  poisonous  alkaloid  of  hemlock, 
Gonium  maculatum.  It  occurs  in  all  parts  of  the  plant,  in 
combination  with  organic  acids,  and  in  association  with  the 
following  allied  bases  : — 


Base. 

Formula. 

11 

Specific 
Gravity. 

Ethyl-piperidine, . 

C7H16N:  or  C6H9(C2Hb)NH 

... 

142-145 

|J  =0-8674 

Conine  (Normal-) 
propyl-piperi-   >- 
dine),                 ) 

CgHi^N ;  or  C6H9(CsH7)NH 

-2-5 

167-170 

1^=0-8625 

Methyl-conine,     . 

C9H19N ;  or  C6H9(C8H7)N(CH8) 

... 

... 

{i|5=0.846 

Conhydrine,  . 

CgHiyNO ;  or  C5H9(CHOH.CH2.CH8)NH 

120-6 

240(225 
at  720 

... 

Paeudo-conhydrine, 

CgHirNO;  or  C5H9(CH3.CH20H.CH)NH 

100-102 

mm.) 
229-231 

... 

Conine    is    an  oily  liquid,  having    a   peculiar   repulsive  odour, 

^  Conine  has  been  prepared  synthetically  by  the  reducing  action  of  sodium 
on  a  boiling  alcoholic  solution  of  ally l-pjTi dine,  C5H4(C3H5)N,  itself 
obtained  from  o-picoline  and  paraldehyde.  The  artificial  base  thus  prepared 
is  identical  in  all  its  properties  vv^ith  the  natural  alkaloid,  except  that  it  is 
optically  inactive.  But  on  introducing  a  crystal  of  the  bitartrate  of  the 
natural  alkaloid  into  a  very  concentrated  solution  of  the  bitartrate  of  the 
inactive  bases,  a  gradual  separation  of  the  bitartrate  of  active  conine  occurs, 
the  free  base  from  which  exhibits  the  same  optical  activity  as  natural  conine. 
The  mother-liquid  contains  a  laevo-rotatory  isomeric  base  (Laden  burg, 
Ber.,  xix.  2578). 


172  PROPERTIES   OF   CONINE. 

suggesting  that  of  a  long-used  and  foul  tobacco-pipe.  "When 
diluted  with  water,  conine  has  a  peculiar  and  characteristic 
"mousy"  odour,  perceptible  in  highly  dilute  solutions.  A  few 
drops  of  an  aqueous  solution  containing  only  1-50,000  of  the 
alkaloid,  if  enclosed  for  a  short  time  in  a  small  test-tube,  is 
stated  byWormley  to  impart  a  marked  mousy  odour  to  the 
contained  air. 

Conine  may  be  distilled  without  change  in  an  atmosphere  of 
hydrogen,  but  undergoes  slight  decomposition  at  high  temperatures 
in  presence  of  air.  It  distils  readily  with  vapour  of  water  or 
alcohol,  and  volatilises  sensibly  at  ordinary  temperatures. 

Conine  is  optically  active,  its  specific  rotation  being  +  13°*8  for 
the  sodium  ray. 

Conine  forms  an  unstable  compound  with  25  per  cent,  of 
water,  the  water  being  expelled  by  heating.  Conine  is  soluble 
in  about  90  parts  of  cold  water,  and  is  readily  dissolved  by 
alcohol,  acetone,  amylic  alcohol,  ether,  chloroform,  petroleum 
ether,  and  benzene.  The  alkaloid  is  removed  with  tolerable 
facility  from  its  aqueous  or  alkaline  solutions  by  agitation  with 
either  of  the  last  five  solvents,  and  may  be  recovered  therefrom 
by  shaking  the  resultant  solution  with  dilute  acid. 

Conine  dissolves  sulphur,  but  not  phosphorus  nor  calcium  chloride. 

Conine  is  colourless  when  freshly  prepared,  but  becomes  yellow 
and  ultimately  resinoid  by  keeping.^  It  is  a  strong  base,  the 
aqueous  solution  being  powerfully  alkaline  in  reaction,  and 
neutralising  acids  perfectly.  The  salts  are  colourless  and  odour- 
less, but  the  peculiar  odour  of  the  free  base  is  immediately 
developed  on  adding  a  fixed  alkali  in  excess. 

If  a  beaker  moistened  with  fuming  hydrochloric  acid  be 
inverted  over  a  watch-glass  containing  a  drop  of  free  conine, 
white  fumes  will  be  produced,  and  the  alkaloid  will  be  con- 
verted after  a  time  into  a  crystalline  hydrochloride^  C^^j^ ^C\. 
(Nicotine  gives  an  amorphous  hydrochloride.)  The  hydrochloride 
is  also  obtained  as  a  brilliant  crystalline  mass  by  dissolving  conine 
in  anhydrous  ether,  and  passing  dry  hydrochloric  acid  gas  through 
the  solution.  The  salt  is  very  soluble  in  water  and  alcohol,  but 
insoluble  in  ether.  It  can  be  heated  to  90°  C.  without  decom- 
position or  loss  of  weight.       It  melts  at  218°. 

The  hydriodide  of  conine  is  anhydrous.  It  can  only  be 
obtained  crystalline  by  the  use  of  pure  hydriodic  acid  free  from 
any  trace  of  iodine.  By  slow  evaporation  the  salt  is  obtainable 
in  large  flat  needles,  which  sublime  when  gently  heated  in  vacuo. 

^  According  to  S c h o rm,  pure  conine  does  not  undergo  any  change  by 
exposure  to  light  {Pharm.  Jour.,  [3],  xii.  363). 


REACTIONS   OF   CONINE.  173 

On  adding  a  large  excess  of  strong  hydrochloric  acid  to  conine, 
a  pale  red  tint  is  produced,  which  gradually  deepens  in  colour. 
Nitric  acid  acts  similarly.  Sulphuric  acid  produces  no  immediate 
change  with  conine,  but  the  mixture  gradually  becomes  purple- 
red,  and  then  olive-green. 

On  exposing  a  drop  of  conine  to  the  vapours  of  bromine 
(avoiding  excess),  it  becomes  rapidly  converted  into  a  mass  of 
white  crystals.  This  behaviour  is  regarded  by  Watts  as  a  proof 
of  the  purity  of  the  alkaloid. 

By  the  treatment  of  conine  with  chromic  acid  mixture,  normal 
butyric  acid  is  produced.  The  reaction  may  be  employed  as 
a  test  for  conine,  as  butyric  acid  has  a  highly  characteristic  odour, 
and  can  be  readily  distilled  ofif  and  further  examined.  Butyric 
acid  also  results  from  the  oxidation  of  conine  by  bromine-water  or 
nitric  acid,  while  permanganate  converts  it  into  picolinic  acid. 

On  distillation  of  conine  hydrochloride  with  zinc-dust,  or  the 
free  base  with  zinc  chloride,  hydrogen  is  evolved  and  a-propyl- 
pyridine  or  conyrine,  Cr^TlJfi^'K^)'N,  formed.  This  base 
boils  at  166°-168°,  and  is  reconverted  into  conine  on  treatment 
with  hydriodic  acid.  (By  prolonged  treatment  with  hydriodic 
acid  conine  is  converted  into  ammonia  and  octane,  CgH^g.) 

Mercuric  chloride  produces  with  conine  a  white  amorphous 
precipitate,  readily  soluble  in  hydrochloric  or  acetic  acid.  (Nico- 
tine gives  a  crystalline  precipitate.)  With  potassio-mercuric 
iodide,  conine  gives  a  voluminous  curdy  precipitate.  Silver  nitrate 
gives  a  brown  precipitate  of  argentic  oxide  with  free  conine,  the 
colour  afterwards  changing  to  black.  (Nicotine  gives  a  white 
precipitate  with  silver  nitrate,  turning  dark  on  exposure  to 
light.)     Conine  cMoroplatinate  is  a  readily  soluble  salt. 

Conine  gives  a  yellow  precipitate  with  phosphomolybdic  acid, 
and  an  orange  precipitate  with  potassio-iodide  of  bismuth. 

Picric  acid  does  not  precipitate  conine  from  solutions  con- 
taining less  than  1  per  1000  of  the  alkaloid,  but  nicotine  is 
precipitated  from  solutions  fifty  times  more  dilute. 

Conine  is  said  to  coagulate  albumin,  thus  differing  from  nicotine. 

If  conine  be  dropped  into  a  solution  of  alloxan,  an  intense 
purple-red  coloration  is  gradually  produced,  and  white  needles 
separate  which  dissolve  with  purple  colour  in  cold  potash 
solution. 

The  alkaloids  occurring  with  conine  in  hemlock  and  its  prepara- 
tions are  precipitated  by  Mayer's  reagent,  picric  acid,  and  iodine 
from  solutions  considerably  more  dilute  than  those  from  which 
conine  itself  is  thrown  down, 

CoNHYDRiNE  lias  the  probable  constitution  of  a  piperidyl- 


174  DERIVATIVES   OF   CONINE. 

e  t  h  y  1  a  1  k  i  n  e,  C5H9(CHOH.CH2.CH3)NH.  It  presents  a  close 
resemblance  to  t  r  o  p  i  n  e,  CgHjgNO,  both  in  composition  and 
chemical  behaviour,  a  fact  which  suggested  to  A.  W.  H  o  f  m  a  n  n 
the  probability  that  it  was  the  product  of  the  hydrolysis  of  a  base 
allied  to  atropine.  From  the  alkaline  liquid  left  after  the  distillation 
of  conine  and  conhydrine,  H  o  f  m  a  n  n  obtained,  by  acidulation  and 
extraction  with  ether,  caffeic  acid,  CgllgO^,  a  body  liaving  the 
constitution  of  a  dihydroxy-cinn  amic  acid. 

Conhydrine  may  be  separated  from  commercial  conine,  in  which 
it  is  not  unfrequently  present,  by  cooling  the  liquid  down  to  5°  C, 
filtering  through  glass  wool,  and  washing  the  separated  crystals  of 
conhydrine  with  petroleum  ether,  in  which  it  is  but  sparingly 
soluble.  Pseudoconhydrine  is  a  base  isomeric  with  con- 
hydrine, but  probably  containing  hydroxy-isopropyl  (Ladenburg, 
Ber.,  xxiv.  1671).  Conhydrine  forms  colourless  glittering  crystals, 
moderately  soluble  in  water,  but  very  soluble  in  alcohol  and  ether. 
It  does  not  react  with  nitrous  acid,  has  an  alkaline  reaction,  and  is 
a  feeble  narcotic  poison.  According  to  "Wertheim,  hemlock 
contains  only  5  to  6  parts  of  conhydrine  for  every  100  of  conine. 

CoNiCEiNES,  CgHjgN.  These  bases  were  obtained  by  A.  W. 
H  0  f  m  a  n  n  by  the  action  of  oxidising  agents  on  conine,  or  of 
dehydrating  agents  on  conhydrine.  When  molecular  proportions  of 
conine  hydrobromide  and  bromine  are  mixed,  the  bromo-deriva- 
tive,  CgHj^KHBr.Brg,  is  obtained.  By  the  regulated  action  of 
caustic  soda  this  yields  CgH^^XBr,  which  by  treatment  with  sul- 
phuric acid  is  decomposed  into  hydrobromic  acid  and  a-coniceine, 
which  is  a  colourless  liquid  of  '893  specific  gravity  at  15°,  boiling 
at  158°,  and  slightly  soluble  in  water.  In  odour  it  closely 
resembles  conine,  but  is  said  to  be  five  or  six  times  as  poisonous ! 
It  is  a  tertiary  base  of  strong  alkaline  reaction,  and  forms  crystal- 
isable  salts.  The  picrate  forms  yellow  needles  melting  at  226°, 
nearly  insoluble  in  cold  water,  and  very  slightly  soluble  in  alcohol, 
a-coniceine  is  partially  reduced  to  conine  by  heating  under  pressure 
with  fuming  hydriodic  acid  and  phosphorus.  y-coniceine  is 
obtained  by  decomposing  the  bromo-derivative  CgH^gNBr  by  an 
alkali.  It  is  a  colourless  liquid  lighter  than  water,  boiling  at  173°, 
distilling  with  steam,  and  said  to  be  twelve  times  as  poisonous  as 
conine  !  It  is  only  slightly  soluble  in  water,  but  the  solution  is 
strongly  alkaline.  y-coniceine  is  a  secondaiy  base  (pages  1,  7) 
yielding  crystalline,  volatile  salts  with  acids,  and  a  characteristic 
double  salt  with  stannic  chloride,  BgHgSnClg,  which  forms  large 
crystals.  ^-coniceine  is  obtained  together  with  a-coniceine  by 
the  action  of  phosphoric  anhydride  or  fuming  hydrochloric  acid 
on  conhydrine  : — CgHi^NG  =  CgH^gN  -|- HgO.     It  forms  very  vola- 


POISONING  BY   HEMLOCK.  175 

tile,  colourless  needles,  melts  at  41°  and  boils  at  168°.  It  is  a 
secondary  base  of  conine-like  odour,  and  is  a  less  active  poison  than 
the  a-modification. 

Poisoning  by  Conine  and  Hemlock. 

Conine  is  an  extremely  powerful  paralytic  poison,  which  acts 
on  the  motor  nerves;  one  drop  is  a  distinctly  poisonous  do^e, 
while  ten  drops  may  be  fatal. 

The  symptoms  produced  by  hemlock  and  conine  are  not  uniform, 
and  cases  of  poisoning  are  not  numerous.  Stupor,  coma,  and 
slight  convulsions  have  been  noticed,  while  in  other  cases  the  chief 
effect  has  been  paralysis  of  the  muscular  system,  especially  of  the 
legs.  The  pupils  are  somewhat  dilated.  After  death  the  lungs 
are  found  filled  with  fluid  blood  and  of  a  dark  colour,  and  the 
stomach  and  intestines  somewhat  congested.  The  posi-morteim 
appearances  are  not  characteristic. 

In  toxicological  inquiries  the  viscera  and  contents  of  the  stomach 
should  be  treated  as  described  under  strychnine,  the  purified  extract 
being  agitated  with  soda  and  ether  instead  of  ammonia  and  chloro- 
form. From  the  ether,  the  alkaloid  may  be  recovered  by  allow- 
ing the  solvent  to  evaporate  spontaneously  in  a  cool  place,  or 
extracted  as  a  salt  by  agitating  the  ether  with  dilute  hydrochloric 
acid.  From  the  purified  salt  of  conine  thus  obtained,  the  free 
base  may  be  again  liberated  by  adding  soda,  and  recognised  by 
the  mousy  odour  of  hemlock  developed  immediately  or  on  warming 
the  liquid. 

Conine  may  also  be  isolated  from  the  viscera  by  the  method 
used  for  the  assay  of  hemlock.  Otto  in  one  case  met  with  a 
volatile  ptomaine,  which  was  very  poisonous,  but  differed  from 
conine  in  its  reaction  with  platinic  chloride.  The  seeds  of  Lupimis 
luteus  (page  177)  contain  alkaloids  somewhat  resembling  conine, 
but  which  do  not  yield  the  characteristic  crystalline  hydrochloride. 
Other  of  the  umhelliferce  besides  conium  are  possessed  of  poisonous 
properties,  but  it  does  not  appear  that  conine  has  been  proved  to  be 
the  active  principle.^ 

^  (EnantJie  crocata,  or  hemlock  wateirdropwort,  is  described  by  A. 
S.  Taylor  as  one  of  the  most  virulent  of  English  vegetable  poisons.  The 
leading  symptoms  produced  are  rapid  insensibility,  bloated  and  livid  coun- 
tenance, convulsive  movements,  stertorous  breathing,  dilated  pupils,  and 
bloody  foam  about  the  mouth  and  nostrils. 

Gicuta  virosa,  water-hemlock  or  cowbane,  produces  symptoms  similar 
to  the  above,  including  the  foaming  at  the  mouth*  It  is  said  to  contain 
c  i  c  u  t  i  n  e. 

Sium  latifoUum  and  S.  angustifoUum  have  been  mistaken  for  water-cress, 
with  fatal  results. 

^thusa  Cynapium,  the  lesser  hemlock  or  fool's  parsley,  appears 


176  ASSAY   OF   HEMLOCK. 

Assay  op  Hemlock  and  its  Preparations. 

Conine  exists  in  all  parts  of  the  common  or  spotted  hemlock, 
Conium  maculatum  (French,  la  Cigue ;  German,  der  Schieliwj). 
It  appears  to  be  most  abundant  in  the  fruit,  the  proportion  increas- 
ing with  the  maturity  of  the  seeds.  In  hemlock  leaves,  R.  K  o  r  d  e  s 
found  0*24,  and  in  the  fruit  0*49  per  cent,  of  alkaloid. 

For  the  extraction  of  conine  from  hemlock,  J.  S  c  h  o  r  m 
(Ber.,  xiv.  1765)  recommends  that  the  fiuit  should  first  be 
swelled  by  hot  water,  and  then  moistened  with  a  strong  solution 
of  sodium  carbonate.  The  product  is  treated  with  steam,  under  a 
pressure  of  three  atmospheres,  as  long  as  the  distillate  has  an 
alkaline  reaction,  when  it  is  neutralised  with  hydrochloric  acid 
and  evaporated  to  a  weak  syrup,  which  is  shaken  with  twice  its 
measure  of  strong  alcohol  and  filtered  from  the  precipitated 
ammonium  chloride.  The  filtrate  is  distilled  at  100°,  a  calculated 
amount  of  caustic  soda  ley  added,  and  the  mixture  agitated  with 
ether.  (The  residual  aqueous  liquid  developes  trimethylamine  on 
prolonged  standing,  especially  in  summer.)  The  ethereal  solution 
deposits  large  crystals  ofconhydrine  when  strongly  cooled.  This 
base  is  somewhat  sj)aringly  soluble  in  ether,  and  on  distilling  the 
solution  passes  over  with  the  ether.  The  conine  remaining  in  the 
retort  is  dehydrated  with  potassium  carbonate,  and  purified  by 
fractional  distillation.  The  first  10  per  cent,  boils  between  110° 
and  168°  C,  and  is  very  impure.  The  next  60  per  cent.,  boiling 
between  168°  and  169°,  is  pure  conine;  while  the  next  20  per 
cent.,  boiling  between  169°  and  180°,  is  impure.  The  thick  dark 
liquid  left  in  retort  contains  conhydrine. 

A  purer  product,  but  somewhat  lower  yield,  is  said  to  be  obtained 
by  exhausting  the  hemlock  fruit  with  acetic  acid,  and  evaporating 
the  solution  to  a  syrup  in  a  vacuum.  Magnesia  is  then  added, 
and  the  mixture  agitated  with  ether,  which  extracts  the  alkaloid. 

Many  specimens  of  conium  leaves  and  seed  are  almost  inert  from 
the  loss  of  their  volatile  active  constituent,  and  hence  a  method  of 
assay  is  of  considerable  importance,  and  ought  to  have  a  place  in 
the  Pharmacopoeia. 

For  the  determination  of  the  conine  and  associated  alkaloids  in 
hemlock,  R.  A.  Cripps  {Pharm..  Jour.,  [3],  xviii.  13,  511) 
recommends  the  following  process : — A  weight  of  5  grammes  of 
the  finely-powdered  fruit  is  mixed  with  an  equal  weight  of  sand, 
and  extracted  with  a  mixture  of  25  c.c.  of  nearly  absolute  alcohol, 

to  contain  an  energetic  poison,  though  this  has  been  disputed  by  H  a  r  1  e  y  (^< 
Thomas's  Hospital  Reports,  new  series,  iv.  63  ;  x.  257),  and  also  by  Tanret, 
who  believes  the  erroneous  statements  respecting  it  to  have  arisen  from  a  con- 
fusion of  the  plant  with  Conium  maculatum,  which  it  closely  resembles. 


ASSAY  OF  CONIUM   PllEPARATlONS.  177 

15  c.c.  of  chloroform,  and  10  c.c.  of  a  saturated  solution  of  dry- 
hydrochloric  acid  gas  in  chloroform.  The  liquid  is  separated  from 
the  marc^  and  agitated  with  two  separate  quantities  of  25  c.c.  of 
distilled  water.  The  aqueous  liquid  now  contains  the  conine  as 
hydrochloride.  It  is  shaken  once  with  chloroform,  then  rendered 
alkaline  with  caustic  soda,  and  extracted  three  times  by  agitation 
with  chloroform.  The  chloroform  is  washed  by  agitation  with 
alkaline  water,  and  is  then  run  into  a  solution  of  hydrochloric  acid 
gas  in  ether.  This  is  evaporated  in  a  current  of  air,  and  the 
residue  dried  at  a  temperature  not  exceeding  90°  C.  The  conine 
hydrochloride  obtained  should  be  crystalline,  and  almost  perfectly 
white.  From  its  weight  the  proportion  of  conine  can  be  calculated, 
163'5  of  the  hydrochloride  representing  127'0  of  the  base.  If, 
after  weighing  the  residue,  the  hydrochloric  acid  be  determined  by 
titration  with  silver  nitrate,  using  potassium  chromate  as  an  indi- 
cator, the  difference  will  be  the  weight  of  alkaloid,  and  the  result 
should  closely  correspond  with  that  previously  calculated. 

The  foregoing  process  may  be  shortened  by  agitating  the  washed 
chloroformic  solution  of  the  conine  as  liberated  by  caustic  soda  with 
water,  and  gradually  adding  decinormal  hydrochloric  acid  until  a 
slight  acid  reaction  to  methyl-orange  is  developed,  which  does  not 
disappear  on  again  shaking.  Each  c.c.  of  decinormal  acid  used 
represents  0'0127  gramme  of  alkaloid,  in  terms  of  conine.  Petro- 
leum spirit  may  be  substituted  for  the  chloroform. 

For  the  estimation  of  the  alkaloids  in  Tincture  of  Oonium,  Fair 
and  Wright  (Pharm.  Jour.,  [3],  xxi.  857)  evaporate  50  c.c.  of 
the  preparation  to  a  low  bulk  at  100°  C.  with  1  c.c.  of  normal 
sulphuric  acid.  The  residual  liquid  is  diluted  somewhat,  and 
twice  shaken  with  chloroform.  It  is  then  rendered  alkaline  with 
ammonia,  and  the  liberated  alkaloids  shaken  out  with  chloroform. 
The  chloroformic  solution  is  freed  from  traces  of  ammonia  by 
agitation  with  water,  separated  and  run  into  a  solution  of  dry 
hydrochloric  acid  gas  in  chloroform,  taking  care  that  the  orifice 
of  the  separator  dips  below  the  surface  of  the  acid  chloroform, 
which  is  then  evaporated,  and  the  residue  dried  at  90°  and 
weighed,  as  recommended  by  Cripps.  The  proportion  of  total 
alkaloid  contained  in  the  tincture  of  conine,  as  assayed  by  this 
process,  is  from  0'07  to  0*10  per  cent.  The  proportion  in  the 
extract  ranges  from  J  to  nearly  3  per  cent. 

^  The  exhaustion  should  be  proved  to  be  complete,  by  treating  the  marc 
with  water,  and  testing  the  solution  with  iodine  and  with  Mayer's  solution, 
neither  of  which  should  produce  more  than  the  faintest  turbidity  ;  and  the 
dried  marc  should  give  a  barely  perceptible  odour  of  conine  when  warmed  with 
caustic  soda. 

VOL.  III.  PART  II.  M 


178  LUPTNTNE. 

Lupine  Alkaloids, 

From  the  different  species  of  lupine  several  alkaloids  have  been 
isolated,  some  of  which,  at  any  rate,  belong  to  the  class  of  volatile 
alkaloids,  and  in  their  odour  and  other  characters  appear  to  be 
related  to  conine. 

LupiNiNE,  G^iH^oNfi^'  0^  C2iH38N2(OH)2  As  isolated  by  G. 
Baumert  from  the  seeds  of  Lupinus  luteus,  lupin ine  is  a  readily 
crystallisable  base,  melting  at  67°'5-68°*5,  and  boiling  with  some 
decomposition  at  255°-261°.  In  a  stream  of  hydrogen  it  distils 
unchanged  at  255°— 257°,  and  is  also  volatile  with  steam.  Lupinine 
has  a  pleasant  apple-like  odour  and  an  extremely  bitter  ta^te, 
the  latter  character  extending  to  its  salts.  It  has  a  paralysing 
effect  on  the  nerve-centres.  Lupinine  is  Isevo-rotatory,  easily 
soluble  in  cold  water  and  alcohol,  but  less  soluble  in  warm  water. 
Erom  its  aqueous  solution  it  is  separated  by  excess  of  caustic  alkali. 
Lupinine  dissolves  readily  in  ether,  chloroform,  and  benzene.  Car- 
bon disulphide  dissolves  the  base  while  acting  chemically  upon  it. 

Lupinine  is  highly  caustic,  and  is  a  strong  base,  liberating 
ammonia  from  its  salts  and  fuming  with  hydrochloric  acid.  B(HC1)2 
forms  large  rhombic  crystals.  BHgPtClg  is  crystalline  and  soluble 
in  water.  The  aurochloride,  B(HAuCl4)2,  forms  needles,  difficultly 
soluble  in  water,  but  readily  in  alcohol.  The  nitrate,  'QQl^O^^^ 
forms  rhombic  crystals,  very  soluble  in  water  and  alcohol. 

Metallic  sodium  dissolves  in  melted  lupinine  with  evolution  of 
hydrogen,  forming  a  sodium-derivative,  decomposed  by 
water  into  lupinine  and  sodium  hydroxide.  When  heated  with 
acetic  anhydride,  lupinine  yields  0<^^^^{G^^O\,  as  an  oil, 
insoluble  in  water  and  very  easily  saponified. 

When  lupinine  is  heated  to  150°- 180°  for  ten  or  twelve  hours 
with  fuming  hydrochloric  acid,  or  the  hydrochloride  to  175°  with 
phosphoric  anhydride,  it  yields  anhydrolupinine,  0211138X20,  as 
a  highly  oxidisable  fluid  base,  smelling  like  conine.  BHgPtOlg 
forms  red  quadratic  tables,  easily  soluble  in  water  and  dilute 
alcohol.  Dianhydrolupinine,  OgjHggNg,  results  when  lupinine  is 
heated  with  fuming  hydrochloric  acid  to  200°  0.  It  is  a  highly 
oxidisable  oil,  boiling  at  220°,  and  forming  a  chloroplatinate, 
crystallising  in  dark  red  needles.  Oxylupinine,  C^^A^o^j^b^  ^^ 
formed,  together  with  anhydrolupinine,  by  the  action  of  phosphoric 
anhydride  on  lupinine  hydrochloride.  It  is  a  yellowish,  disagree- 
able smelling  oil,  boiling  with  some  decomposition  at  215°. 

Arqininb,  OgH^^N^Og,  is  contained  in  the  seeds  of  L.  luteus 
which  have  germinated  in  the  dark.  It  forms  crystalline  salts, 
evolves  nitrogen  with  nitrous  acid,  and  yields  urea  when  boiled 
with  baryta-water. 


LUPINE  ALKALOIDS.  179 

LuPiNiDiNB,  CgH^gN,  is  a  base  found  by  B  a  u  m  e  r  t  in  the 
yellow  lupine.  It  forms  a  volatile,  oxidisable,  viscous  oil, 
having  an  odour  of  hemlock.  It  is  intensely  bitter  and  feebly 
poisonous,  producing  symptoms  like  those  of  curare.  Lupinidine 
forms  a  crystalline  hydrate,  BjHgO,  very  insoluble  in  water.  The 
salts  are  crystallisable.     No  acetyl-derivative  is  obtainable. 

LuPANiNE,  C15H24N2O,  is  an  alkaloid  obtained  by  M.  H  a  g  e  n 
{LieUgs  Annalen,  ccxxx.  367  ;  Jour.  Ghem.  Soc,  1.  163)  from  the 
seeds  of  the  blue  lupine,  Lupinus  angusH/oUus,  which  are 
stated  not  to  contain  lupinine  or  lupinidine.  It  is  described  as  a 
pale  yellow,  honey -like  syrup,  with  green  fluorescence,  intensely 
bitter  taste,  and  an  unpleasant  odour  like  that  of  hemlock. 
Lupanine  does  not  boil  at  290°,  even  under  the  reduced  pressure  of 
130  mm.  It  has  a  strong  alkaline  reaction,  attacks  the  skin,  expels 
ammonia  from  its  salts,  and  forms  with  hydrochloric  acid  white 
fumes  of  the  hydrochloride.  With  excess  of  cold  water,  lupanine 
forms  a  turbid  solution,  from  which  the  base  is  almost  entirely  separ- 
ated on  heating.  It  dissolves  with  difficulty  in  cold  alcohol,  but 
readily  in  ether,  chloroform,  and  petroleum  spirit.  Lupanine  hydro- 
chloride^ BHCl-f  2aq.,  forms  hygroscopic,  quadratic  crystals,  melting 
at  127°,  and  soluble  in  alcohol  but  not  in  ether.  BHgPtClg  is  not 
distinctly  crystalline.  BHAuCl^  forms  golden  needles,  insoluble  in 
water,  alcohol,  or  ether.  From  solutions  of  its  salts,  lupanine  is 
precipitated  by  caustic  potash  and  soda,  but  not  by  ammonia. 

From  the  seeds  of  Lupinus  alhus,  C  a  m  p  a  n  i  isolated  a  poisonous 
liquid  alkaloid,  boiling  at  210°-218°.  From  the  same  source 
B  e  t  e  1 11  obtained  a  crystallisable  base. 

According  to  0.  Ke liner  (Bied.  Centr.^  x.  97)  lupine  seeds 
can  be  deprived  of  the  whole  of  their  bitter  constituents,  and 
rendered  much  more  palatable  and  wholesome,  by  soaking  them 
in  water  for  twenty-four  hours,  steaming  them  for  one  hour,  and 
then  washing  them  for  two  days.  Ktihn  has  shown  that  the 
substances  which  cause  lupine  sickness  are  destroyed  by  steaming. 

Nicotine.     Nicotia.     CjoHi^Ng ;  or  CgHyN.CgHyN. 

Nico-tine  has  the  constitution  of  ahexahydro-dipyridyl 
(see  page  164).  It  is  the  poisonous  basic  principle  of  tobacco,  in 
which  it  exists  combined  with  malic  and  citric  acids  (compare  page 
184),  in  proportions  varying  within  very  wide  limits. 

Pure  nicotine  is  a  colourless,  oily  fluid  of  I'Oll  specific  gravity 
at  15°  C.  On  prolonged  exposure  to  air  it  becomes  yellow,  and 
eventually  resinoid.  It  has  a  sharp  caustic  taste,  is  intensely 
poisonous,  and  has  a  strong  and  unpleasant  odour,  recalling  that  of 
tobacco.     Nicotine  boils  at  about   250°  C,  with  partial  decom- 


180 


CHARACTERS   OF    NICOTINE. 


position,  but  it  distils  readily  with  the  vapour  of  water  or  alcohol, 
and  volatilises  to  a  notable  extent  at  the  ordinary  temperature. 
Nicotine  absorbs  moisture  from  the  air,  and  evolves  heat  when 
mixed  with  water,  diminution  in  volume  simultaneously  occurring.^ 
Skalweit  (Ber.,  xiv.  1809)  has  given  the  following  figures 
showing  the  specific  gravity  of  mixtures  of  nicotine  and  water. 
His  results  point  to  the  existence  of  a  hydrate  of  nicotine. 


Mcotine. 

Water. 

Specific  Gravity 
at  lb'  a 

100 

0 

1-011 

100 

5 

1-017 

100 

10 

1-024 

100 

20 

1-030 

100 

30 

1-034 

100 

40 

1-037 

100 

50 

1-040 

100 

60 

1-038 

100 

70 

1-033 

Nicotine  has  a  powerful  laevo-rotatory  action  on  polarised  light, 
the  value  of  Sj,  in  20  per  cent,  aqueous  solution  being,  according 
to  Pribram,  — 161°*55.  The  rotation  diminishes  rapidly  but 
irregularly  by  further  dilution.  Thus  for  a  4  per  cent,  solution 
the  value  S^  is  —  77°"03,  while  below  this  strength  an  increase  is 
observed,  S^  being  —  79°'32  for  a  solution  of  0*8826  specific 
gravity.  The  rotation  is  affected  by  time,  not  reaching  its  maximum 
for  48  hours  (Ber.,  xx.  1840). 

The  aqueous  solution  of  nicotine  is  powerfully  alkaline  in  reaction. 
The  nicotine  is  partially  separated  by  addition  of  excess  of  caustic 
potash  or  soda  (compare  pyridine).  Nicotine  in  aqueous  solution, 
and  in  the  absence  of  other  free  base,  can  be  determined  by 
titration  with  standard  acid  and  methyl-orange. 

Nicotine  forms  two  classes  of  salts.  The  m  on  acid  salts  are 
stable  and  neutral  to  litmus  and  methyl-orange,  but  the  diacid  salts 
have  an  acid  reaction.  Most  of  the  salts  of  nicotine  crystallise 
with  difficulty.  The  acid  tartrate,  C-^QK^^1^2i^^^QOQ\-\-2a.q.,  is 
an  exception,  and  forms  handsome  tufts  when  ether  is  added  to  its 
alcoholic  solution. 

Detection  and  Determination  of  Nicotine. 

Alcohol  dissolves  nicotine  in  all  proportions,  and  on  evaporating 

1  When  water  is  added  to  solution  of  nicotine  containing  less  than  20  per 
cent,  of  base,  the  mixture  becomes  turbid  and  clears  only  on  long  standing. 
On  heating  to  40°  the  liquid  clears  rapidly,  but  becomes  again  turbid  when 
cooled  or  further  heated  to  60°.  Between  50°  and  60°  the  turbidity  amounts 
to  milkiness,  which  disappears  when  the  liquid  is  cooled  below  50°.  At  70* 
the  nicotine  separates  in  part  as  an  oily  layer. 


REACTIONS  OF  NICOTINE.  181 

or  distilling  the  solution  the  alkaloid  is  found  chiefly  in  the  first 
fractions.  It  is  extracted  from  its  aqueous  alkaline  solutions  by 
agitation  with  ether,  chloroform,  benzene,  amylic  alcohol,  or 
petroleum  spirit,  and  may  be  recovered  from  the  solvent  by 
separating  and  agitating  with  dilute  acids.  If  oxalic  acid  be 
employed,  the  resultant  solution  may  be  evaporated  to  dryness  and 
treated  with  alcohol,  which  dissolves  the  nicotine  oxalate  while 
leaving  any  ammonium  oxalate  undissolved.  After  again  removing 
the  alcohol  by  evaporation,  the  nicotine  may  be  liberated  from 
the  warm  liquid  by  adding  excess  of  caustic  soda,  when  the 
characteristic  tobacco-like  smell  of  nicotine  will  be  observed,  and 
the  alkaloid  can  be  obtained  pure  by  distilling  the  liquid  with 
water,  or  agitating  it  with  ether  and  allowing  the  separated  solvent 
to  evaporate  spontaneously  in  a  cool  place. 

Treated  with  nitric  acid,  nicotine  yields  a  thick  reddish  liquid. 
Sulphuric  acid  produces  no  change  in  the  cold,  but  a  brown  colour 
is  developed  on  heating. 

On  dissolving  nicotine  in  dilute  hydrochloric  acid,  and  adding 
platinic  chloride,  nicotine  chloroplatinate,  C^QHj^NgjHgPtClg,  is 
thrown  down  as  a  sparingly  soluble,  yellowish,  crystalline  com- 
pound. The  precipitate  is  soluble  in  hot  water,  especially  in 
presence  of  free  hydrochloric  acid.  Addition  of  alcohol  increases 
the  delicacy  of  the  test,  and  the  formation  of  the  precipitate  is 
much  facilitated  by  stirring  the  liquid.  Ammonia  gives  a  similar 
reaction,  but  c  o  n  i  n  e  yields  no  precipitate  with  platinic  chloride. 

Picric  acid,  if  added  in  excess  to  solution  of  nicotine,  throws 
down  nicotine  picrate  as  an  amorphous  yellow  precipitate,  which 
rapidly  changes  to  a  mass  of  crystalline  tufts,  even  in  presence  of 
foreign  organic  matter. 

Nicotine  is  precipitated  by  Mayer's  reagent  (page  138)  from 
very  dilute  solutions ;  and,  by  operating  in  strongly  acid  liquids, 
Zinoffsky  obtained  very  good  quantitative  results.  The  formula 
of  the  precipitate  is  CjoH^^gNgHgl^,  and  1  c.c.  of  the  reagent  repre- 
sents 0-00202  gramme  of  nicotine. 

On  adding  mercuric  chloride  to  a  solution  of  nicotine  a  white 
crystalline  precipitate  is  produced,  soluble  in  dilute  hydrochloric  or 
acetic  acid.  This  is  the  most  characteristic  reaction  of  nicotine. 
Strychnine  produces  a  similar  precipitate,  nearly  insoluble  in 
acetic  acid.  Many  other  alkaloids  are  precipitated,  but  the  com- 
pounds are  almost  invariably  amorphous.  This  is  the  case  with  the 
precipitate  produced  by  conine,  which  is  almost  the  only  alkaloid 
which  will  distil  over  with  nicotine  on  boiling  the  solution  with  a 
slight  excess  of  caustic  soda.  Ammonia,  however,  behaves  like 
nicotine,  and  must,  if  necessary,  be  separated  before  applying  the 


182  DETERMINATION   OF   NICOTINE. 

test.  Ammonia  is  sharply  distinguished  from  nicotine,  conine,  and 
lobeline  by  adding  a  solution  of  iodine  in  iodide  of  potassium  to 
the  slightly  acidulated  solution  of  the  base.  Ammonia  produces  no 
change,  but  with  either  of  the  vegetable  alkaloids  a  brown  or  brownish 
red  precipitate  will  result.  Iodine  solution  will  detect  1  of  nicotine 
in  250,000,  and  is  the  most  delicate  reagent  known  for  the  alkaloid. 

Solutions  of  nicotine  are  not  precipitated  by  chromates,  ferro- 
cyanides,  ferricyanides  or  thiocyanates,  nor  by  gallic  acid.  With 
gallotannic  acid  an  aqueous  solution  of  nicotine  yields  a  white, 
amorphous  precipitate,  which  readily  dissolves  on  cautious  addition 
of  hydrochloric  acid,  but  is  again  precipitated  by  further  addition 
of  acid,  and  is  then  insoluble  even  in  a  large  excess.  Tannate 
of  nicotine  is  readily  soluble  also  in  acetic  and  nitric  acids,  but  is 
not  reprecipitated  on  adding  an  excess. 

A  variety  of  processes  have  been  devised  for  the  determination 
of  nicotine  in  tobacco  and  its  preparations.  The  problem  is  com- 
plicated by  the  presence  of  ammonium  salts,  by  the  difficulty  of 
completely  extracting  nicotine  from  aqueous  liquids  by  agitation 
with  immiscible  solvents,  and  by  the  tendency  to  form  an  emulsion 
when  these  are  used,  owing  to  the  presence  of  pectinous  mattei; 
The  methods  proposed  have  been  reviewed  by  J.  B  i  e  1  {Pharm. 
Zeit.  Russ.y  xxvii.  3;  Analyst,  xiii.  97),  who  recommends  the 
following  process,  which  is  a  modification  of  that  proposed  by 
Kiss  ling: — 100  grammes  of  powdered  tobacco-leaves,  or 
10  to  20  grammes  of  extract  of  tobacco,  are  mixed  with  slaked 
lime  and  distilled  in  a  current  of  steam  until  the  condensed 
steam  is  no  longer  alkaline.  The  distillate,  which  will  measure 
about  I  litre,  is  rendered  faintly  acid  with  dilute  sulphuric  acid, 
evaporated  to  50  c.c,  made  alkaline  with  caustic  soda,  and  agitated 
six  times  with  ether,  using  20  c.c.  each  time.  Biel  then  distils 
off  the  greater  part  of  ether  slowly,  adds  excess  of  decinormal 
sulphuric  acid,  and  titrates  back  with  decinormal  soda,  using 
rosolic  acid  as  an  indicator.  The  object  in  distilling  off  the  ether 
is  to  get  rid  of  any  traces  of  ammonia  which  may  be  present ;  but 
it  is  difficult  to  do  this  without  risking  the  volatilisation  of  some  of 
the  nicotine.  It  is  preferable  to  titrate  the  unconcentrated  ethereal 
solution  by  gradually  adding  decinormal  sulphuric  acid,  using 
methyl-orange  as  an  indicator,  and  agitating  between  each  addition. 
Each  c.c.  of  decinormal  acid  neutralised  represents  0*0162  gramme 
of  nicotine.  The  results  will  be  high  if  ammonia  be  present,  and 
in  such  case  the  neutralised  aqueous  liquid  should  be  separated 
from  the  ether,  and  evaporated  to  dryness  at  100°.  The  residue 
is  wei(^hed  and  treated  with  absolute  alcohol,  which  will  dissolve 
the  sulphate  of  nicotine,  while  any  ammonium  sulphate  will  be 


POISOKING  BY  NICOTINE.  183 

left  insoluble,  and  its  weight  can  be  deducted  from  the  weight  of  the 
mixed  sulphates  previously  found,  the  difference  being  the  sulphate 
of  nicotine.  The  result  may  be  confirmed  by  adding  phenol- 
phthalein  to  the  alcoholic  solution  of  nicotine  sulphate  and 
titrating  with  decinormal  alkali,  which  will  react  just  as  if  the 
sulphuric  acid  were  uncombined. 

From  Conine,  nicotine  is  distinguished  by  its  odour,  by  being 
heavier  instead  of  lighter  than  water,  and  by  the  reactions  with 
hydrochloric  acid  gas,  mercuric  chloride,  argentic  nitrate,  platinic 
chloride,  and  picric  acid  (see  above,  and  page  181). 

Poisoning  by  Nicotine  and  Tobacco. 

Nicotine  is  one  of  the  most  violent  poisons  known.  Only  a  few 
instances  are  on  record  of  poisoning  of  the  human  subject  by  the 
pure  alkaloid,  but  the  effects  of  tobacco,  which  owes  its  poisonous 
properties  entirely  to  nicotine,  are  well  known.^  Impure  solutions 
of  nicotine  and  infusions  of  tobacco  are  employed  as  insecticides. 

"The  usual  effects  of  a  poisonous  dose  of  tobacco,  when  taken 
into  the  stomach,  are  confusion  in  the  head,  paleness  of  the  coun- 
tenance, vertigo,  nausea,  severe  retching  and  vomiting,  heat  in  the 
stomach,  great  anxiety,  a  sense  of  sinking  at  the  pit  of  the 
stomach  with  extreme  prostration,  trembling  of  the  limbs,  and 
sometimes  violent  purging.  The  pulse  is  small,  feeble,  and  almost 
imperceptible ;  the  respiration  difficult,  and  the  skin  cold  and 
clammy ;  the  pupils  are  generally  dilated,  but  sometimes  con- 
tracted, and  the  vision  is  usually  more  or  less  impaired.  Death  is 
often  preceded  by  convulsions  and  paralysis  "  (T.  G.  "W  o  r  m  1  e  y, 
Micro-chemistry  of  Poisons). 

In  toxicological  investigations,  nicotine  may  be  isolated  from  the 
viscera  in  the  same  manner  as  conine  (pages  170, 175).  An  alterna- 
tive method  is  to  digest  the  suspected  matters  with  water  acidulated 
with  acetic  acid,  and  treat  the  filtered  liquid  with  excess  of  lead 
acetate.  The  liquid  is  again  filtered,  the  lead  removed  from  the 
filtrate  by  passing  sulphuretted  hydrogen,  and  the  clear  solution 
treated  with  caustic  soda,  separated  from  any  precipitate,  and 
distilled,  when  a  fluid  having  the  odour  and  exhibiting  the 
reactions  of  nicotine  will  be  obtained.  Any  supposed  nicotine 
which  may  be  isolated  should  be  tested  by  placing  it  on  the  tongue 
of  a  young  rabbit  or  small  bird,  when  tremors,  paralysis,   and 

^  "When  tobacco  is  smoked,  the  greater  part  of  the  nicotine  is  converted 
into  pyridine  and  other  pyrogenous  compounds,  and  the  entire  decomposition 
of  the  nicotine  is  sometimes  asserted  ;  but  M  e  1  s  e  n  s  appears  to  have  fully 
proved  the  presence  of  unchanged  nicotine  in  tobacco  smoke  in  a  proportion 
equal  to  about  one-seventh  of  that  present  in  the  original  tobacco  (compare 
page  193). 


184 


COMPOSITION   OF  TOBACCO. 


convulsions  will  rapidly  ensue.     Nicotine  appears  to  be  unchanged 

by  putrefaction,  and  hence  may  be  detected  in  the  tissues  long 

after  death. 

Tobacco  (French,  le  Tahac  ;  German,  der  Tahak), 

Tobacco  is  the  dried  leaf  of  Nicotianum  Tabacum  and  allied 

species.^ 

According  to  S.  W.  Johnson,  a  good  crop  of  tobacco,  yielding 

1260  lbs.  of  dry  leaf  and  1110  lbs.  of  dry  stalk,  removes  from  the 

soil  the  following  constituents  in  lbs.  per  acre  : — 


Constituents. 


so,,      .      .      .      . 

Ms 

CaO 

MgO,     .... 

K2O 

NaaO 

Sum  of  Ash  Constituents, 

Nitrogen, 


Leaves. 


14 

n 

73 

17 

71 

5 

206 


Stalks. 


15 
15 
2 
47 
10 

95J 


Total. 


17 

22rJ 

88 

19 

118 

15 

SOli 

82 


As  the  stalks  are  returned  to  the  land,  tobacco  is  not  a  very 
exhausting  crop,  but  requires  abundant  manuring,  since  the  period 
of  growth  does  not  exceed  three  months.  Hence,  rye  may  be 
advantageously  sown  as  soon  as  the  tobacco  is  off,  and  ploughed  in 
as  a  green  crop  when  cultivation  for  tobacco  commences. 

Besides  cellulose,  albuminoid  compounds,  pectic  acid,  gum- 
resins,  and  other  ordinary  plant-constituents,  the  leaf  of  tobacco 
contains  a  peculiai  volatile,  crystalline  principle  called  nico- 
tianin  or  tobacco-camphor,  to  which  the  formula 
^23^32-^2^3  ^^^  been  attributed.  Tobacco  also  contains  the 
volatile  alkaloid  nicotine,  which  is  apparently  peculiar  to  the 
genus.  This  base  exists  in  combination  with  malic  acid,  but 
the  presence  of  citrates,  acetates,  and  oxalates  has  also 
been  established.^  Fresh  tobacco-leaves  (especially  the  midribs) 
contain  a  notable  proportion  of  nitrates,  but  these  salts  are 
said  to  disappear  during  the  process  of  fermentation  to  which 
manufactured  tobacco  is  subjected.  This  fermentation  has  for 
its  object  the  destruction  or  modification  of  some  of  the  natural 

1  The  genus  Nicotiana  contains  more  than  70  species.  N.  Tabacum  yields 
the  tobacco  of  Havana,  Cuba,  France,  Holland,  Belgium,  &c.  N.  rustica 
furnishes  East  Indian  tobacco,  and  the  kinds  known  as  Latakia  and  Turkish 
tobacco.     Tumbekior  Persian  tobacco  is  the  product  of  N.  Persica. 

*  From  100  grammes  of  dried  tobacco-leaves,  G  0  u  p  e  1  obtained  from  3  to  4 
grammes  of  acid  malate  of  ammonium.     J.  Takayama  {Chem.  News,  1. 


OKGANIC   ACIDS  IN  TOBACCO. 


185 


-constituents,  and  the  formation  of  "  ferment  oils,"  which  probably 
•contribute    to     the    aroma,    especially    when    saccharine     matter, 


300)  obtained  the  following  percentage  results  by  the   analysis  of  Japanese 
tobacco : — 


Nagato. 

Shimozuki. 

Settzu. 

Osumi. 

Water, 

6-41 

10-01 

7-63 

13-18 

Ash,       . 

15-76 

8-45 

20-71 

9-80 

Nicotine, 

2-45 

3  02 

3-92 

1-89 

Acetic  acid 

0-05 

0  04 

0-01 

0  08 

Oxalic  acid, 

trace 

0-27 

0-25 

trace 

Malic  acid, 

0-79 

102 

183 

2-98 

Citric  acid, 

0-62 

0-59 

0-92 

0-89 

Pectic  acid, 

1-24 

6-84 

7-42 

2-35 

In  the  above  analyses,  the  nicotine  was  extracted  by  ammoniacal  ether, 
the  solvent  distilled  off,  and  the  nicotine  in  the  residue  determined  by 
titration.  For  the  acetic  acid,  the  powdered  tobacco  was  moistened  with 
water  and  tartaric  acid,  and  distilled  in  a  current  of  steam,  the  acetic  acid 
being  determined  in  the  distillate.  For  the  fixed  organic  acids,  10  grammes 
of  the  sample  was  moistened  with  sulphuric  acid  in  the  quantity  requisite 
to  combine  with  the  bases  (as  indicated  by  the  carbonates  in  the  ash),  and 
exhausted  with  ether.  From  the  ethereal  solution  the  acids  were  extracted 
by  a  small  quantity  of  water,  the  separated  aqueous  liquid  rendered  alkaline 
with  ammonia,  acidulated  with  acetic  acid,  and  the  oxalic  acid  precipitated 
by  adding  calcium  acetate.  To  the  filtrate,  a  dilute  solution  of  lead  acetate 
was  gradually  added,  until  a  test  quantity  of  1  c.c.  of  the  supernatant  liquid 
gave,  on  further  addition  of  lead  acetate,  a  precipitate  which  was  completely 
soluble  in  a  few  drops  of  acetic  acid.  The  liquid  was  then  filtered,  and 
the  precipitate  of  lead  citrate  washed  with  water  containing  a  little  lead 
acetate  and  acetic  acid,  and  then  with  alcohol,  the  washings  being  kept 
separate.  The  citric  acid  was  deduced  from  the  weight  of  lead  oxide  left 
on  igniting  the  precipitate.  From  the  filtrate,  the  malic  acid  was  precipitated 
by  excess  of  lead  acetate  solution,  and  its  amount  deduced  from  the  weight 
of  lead  oxide  left  on  ignition.  The  washings  from  the  precipitate  of  lead 
citrate  were  boiled  to  expel  alcohol  and  treated  with  excess  of  lead  acetate, 
the  precipitate  being  regarded  as  a  mixture  of  lead  citrate  and  malate  in 
-equal  proportions  (compare  Vol.  I.  page  434). 

The  pectic  acid  was  determined  by  exhausting  10  grammes  of  tobacco  with 
rectified  spirit  containing  one-fourth  of  its  volume  of  concentrated  hydrochloric 
acid.  The  residue  was  washed  with  spirit  till  the  hydrochloric  acid  was 
wholly  removed,  and  then  treated  with  a  solution  of  a  known  weight  of 
ammonium  oxalate,  by  which  the  pectic  acid  was  dissolved.  After  digesting 
for  two  hours  at  35°,  the  liquid  was  filtered,  the  residue  washed,  and  the 
filtrate  diluted  to  1  litre.  An  aliquot  part  of  this  was  precipitated  by  calcium 
acetate,  and  the  precipitate  washed  and  dried  at  100°.  The  weight  of  lime 
left  on  igniting  the  precipitate  was  then  ascertained.  The  weight  of  CaO 
and  the  oxalate  in  the  precipitate  being  known,  the  pectic  acid  corresponded 
to  the  difference. 


186 


MANUFACTURE   OF  TOBACCO. 


liquorice  or  alcohol  is  added  during  the  maceration  to  which 
the  tobacco  is  subjected.^ 

As  sold  by  the  farmers,  the  tobacco-leaves  contain  about  30 
per  cent,  of  water.  When  the  fresh  leaf  is  simply  dried,  the 
product  is  yellow,  the  brown  colour  of  commercial  tobacco  being 
due  to  the  regulated  fermentation  already  alluded  to.  The  un- 
manufactured tobacco  imported  into  England  is  converted  into 
roll  or  spun  tobacco,  cut  tobacco,  and  cigars,  the  refuse  being 
used  for  making  snuff.  In  the  manufacture  of  roll-tobacco,  the 
leaves  are  moistened  with  water,  spun  into  various  sizes  of  twist, 
made  up  into  rolls,  and  pressed.  The  liquid  or  juice  which 
exudes  is  used  as  a  sheep-dip.  Cut  tobacco  is  made  by 
moistening  the  leaves,  cutting  them  to  the  required  size,  and 
drying  on  plates ;  or  it  may  be  made  into  cakes  first,  and  after- 
wards cut.  The  Excise  regulations  prohibit  the  use  of  any  foreign 
matter  in  manufacturing  tobacco,  besides  water  and  a  little  oil. 
Hence,  except  in  the  proportion  of  water,  which  is  not  allowed 
to  exceed  35  per  cent,  (as  estimated  by  drying  at  100°  C),  there 
is  no  tangible  diiference  between  manufactured  tobacco  and  the 
dried  leaves  imported.  The  proportion  of  nicotine  in  tobacco 
does  not  appear  to  be  an  index  of  the  quality. 

J.  Clark  {Jour.  Soc.  Chem.  Ind.,  iii.  554)  has  published  the 
percentages  of  ash  yielded  by  the  ignition  of  twenty-one  authentic 


In  100  Parts  of  the  Dry  Substance. 

Total  Ash. 

Soluble  Ash, 
"Alkaline  Salts." 

Sand. 

Whole  Leaf  -.— 

Highest 

Lowest, 

Average, 

Lamina  :— 

Highest,             .... 

Lowest, 

Average,  .  .  .  . 
Midrib  :— 

Highest 

Lowest,       ... 

Average 

30-80* 

13-79 

20-32 

31-07  * 

12-47 

19-21 

80-37  * 

15-44 

21-92 

11-37 
2-40t 
6-47 

8-99 

l-66t 

4-98 

20-01 

4-63 

11-41 

12-32  ♦ 
0-13 
2-48 

14-41* 
0-09 
2-86 

4-91* 

012 

1-15 

*  Paraguay  Tobacco.  t  Chinese  Tobacco. 

samples  of  representative  tobacco-leaves.     The  table  is  an  abstract 
of  his  figures,  which  in  all  cases  refer  to  the  leaf  dried  at  100°  C 

^  Schizomycetes  occur  in  fermented  tobacco  in  large  numbers,  but  the 
number  of  species  is  very  limited.  Trial  experiments  by  E.  Such  si  and, 
with  foreign  ferments  on  German  tobacco-leaves,  yielded  a  tobacco  not  recog- 
nisable as  of  German  origin. 


ASH  OF  TOBACCO. 


187 


As  the  composition  of  the  laminae  and  of  the  stem  or  midriTj  of 
the  leaf  differ  materially,  these  were  carefully  separated  before 
analysis. 

E.  Quajat  {Bied.  Centr.,  1880,  p.  345)  found  the  aah  of 
fourteen  samples  of  dry  tobacco  (including  both  superior  amd 
common  kinds)  to  range  from  31*03  per  cent,  in  a  Bassano  sample 
to  17*11  in  Virginian  and  16*78  per  cent,  in  Turkish.  He  con- 
siders that  the  quality  of  tobacco  varies  inversely  with  the  ash, 
but  N  e  s  s  1  e  r  recognises  no  relation  between  the  two. 

Irby  and  Cabell  (Ghem.  News,  xxx.  117)  have  published 
the  figures  obtained  by  the  analysis  of  six  typical  samples  of 
Virginian  tobacco.  All  were  in  the  leaf  state,  free  from  stalk,  but 
retaining  the  midrib.  No.  1  was  light  yellow  tobacco,  "  coal-cured 
wrappers"  for  cigars ;  No.  2,  light  yellow,  "  fine  smoking"  tobacco ; 
No.  3  was  medium  brown  colour,  "  sweet  fillers"  for  cigars ;  No.  4 
was  dark,  "Austrian  and  Italian  cigar  wrappers;"  No.  5,  dark 
"English  shipping;"  and  No,  6,  dark,  "exported  to  France  for 
snuff."     These  samples  when  air-dried  yielded : — 


No.  1. 

No.  2. 

No.  8. 

No,  4. 

No.  5. 

No.  6. 

Moisture,  per  cent., 

Ash,  total,  per  cent,  on  tobacco,    . 
„    Soluble  in  HCl,  per  100  of  ash, 
„    Sand  and  charcoal,     „        „ 
„    Carbon  dioxide,         „        ,, 

7-91 
11-80 
70-71 

5-30 
23-99 

1-00 
15-39 
63-17 
14-69 
22-14 

11-67 
18-52 
60-93 
16-98 
22-09 

9-93 
16-31 
84-40 
7-92 
7-68 

13-74 
18-18 
64-53 
8-82 
26-65 

9-71 
15-90 
66-66 

8-97 
24-87 

Deducting  the  sand,  carbon,  and  carbon  dioxide,  as  also  the 
small  proportions  of  alumina  and  ferric  oxide  found  in  the  portion 
of  the  ash  soluble  in  acid,  the  "  pure  ash"  of  the  tobacco  was 
calculated.  The  total  nitrogen  was  determined  by  the  absolute 
method  of  Dumas,  and  the  nicotine  by  Mayer's  solution,  with 
the  following  results,  expressed  on  100  parts  of  tobacco  dried  at 
100°  C,:— 


No.  1, 

No.  2. 

No.  3. 

No.  4, 

No.  5. 

No.  6. 

Aver- 
age, 

Pure  ash,     .... 
Total  nitrogen,   . 
Nicotine,     .... 
Nitrogen  in  forms  other  \ 

than  nicotine,         .         / 
Percentage  of  total  nitro-\ 

gen  present  as  nicotine,  / 

8-94 
3-18 
3-32 

2-61 
18-2 

9-29 
2-63 
3-59 

2-01 
23-6 

12-34 
3-72 
5-28 

2-81 
24-5 

14-84 
5-76 
7-09 

4-54 
21-3 

13-39 
5-33 
6-20 

4-26 
20-1 

11-06 
5-26 
8-86 

3-73 
28-9 

11-64 
4-32 
5-72 

3-33 

22-8 

The  following  table  shows  the  average  proportions  of  nitrogen 


188 


ASH   OF  TOBACCO. 


and  ash,  and  the  composition  of  the  latter  in  tobacco  from  various 

sources : — 


Observer 

Number  of  specimens  con-  ) 
tributing  to  average,         ) 
Nitrogen,  per  cent.,     . 
"  Pure  ash,"  per  cent., 

Percentage  composition  qf 
ash— 

Si02,  . 

CI,  .       . 

SOo,  .       .        . 

P2O5,  .       .       . 

K2O, 

NagO,  . 

CaO, 

MgO,  . 


NEW 
England. 

European 

VIEQINIA. 

KENTUCKY. 

(including 
Turkish). 

Irby&CabelL 

Peter. 

S.W.Johnson. 

E.  Wolff. 

6 

30 

12 

13 

4-32 

... 

4-24 

11-64 

12-83 

16-56 

... 

1-72 

2-73 

0-84 

10-29 

2-81 

3-74 

9-36 

4-92 

5-49 

4-21 

6-58 

4-30 

3-30 

4-99 

3-56 

3-21 

35-58 

37-57 

34-96 

18-01 

2-78 

2-10 

1-99 

4-29 

37-60 

35-31 

34-48 

43-51 

10-72 

9-35 

8-21 

11-46 

Will  and  Fresenius  (Ann.  Chem.  Pharm.,  1.  387)  have 
recorded  the  results  of  their  analyses  of  the  ash  of  a  number  of 
samples  of  Hungarian  tobacco,  and  Schloesing  {Jour.  Pract 
Chem.,  Ixxxi.  148)  the  proportions  of  potash,  lime,  magnesia,  sul- 
phates, and  chlorides  in  the  ash  of  tobacco  grown  on  different  soils. 
The  proportion  and  composition  of  the  ash  of  English  tobacco  has 
been  investigated  by  A.  Wingham  (Jour.  Sac.  Chem.  Ind.^  vi. 
76,  400),  of  Indian  and  Burmese  tobaccos  by  K..  Romanis 
{Chem.  News,  xlvi.  248),  and  of  various  kinds  of  tobacco  grown  in 
Japan  by  J.  Takayama  (Chem.  Neios,  1.  301),  and  F e s c a  and 
Imai  (Jour.  Soc.  Chem.  Ind.,  vii.  759). 

The  combustibility  of  tobacco  is  profoundly  affected  by  the  pro- 
portion and  nature  of  the  universal  constituents,  especially  the 
calcium  and  potassium,  and  the  forms  of  combination  in  which 
these  metals  occur.  The  ash  of  the  more  combustible  tobaccos  is 
comparatively  rich  in  potassium  carbonate,  showing  the  presence 
of  a  large  proportion  of  organic  salts  of  potassium  in  the  original 
tobacco,  while  the  ash  of  tobacco  of  inferior  burning  quality  con- 
tains a  larger  proportion  of  sulphates  or  chlorides,  and  hence  pro- 
portionately less  alkaline  carbonates.  According  to  Schloesing 
and  N  e  s  s  1  e  r  tobacco  burns  best  when  it  contains  a  considerable 
proportion  of  potassium  malate,  which  is  a  natural  constituent  of 
the  leaf;  but  the  effect  may  be  imitated,  and  a  slow  burning 
tobacco  improved,  by  the  addition  of  potassium  acetate  or  other 
organic  salt  of  potassium,  while  the  combustibility  may  be  dimin- 
ished by  addition  of  sulphate  of  calcium  or  magnesium.  According 
toE.  R.  Durrwell  the  whiteness  of  the  ash  of  good  tobacco  is 


COMBUSTIBILITY   OF   TOBACCO. 


189 


due  to  the  presence  of  a  large  proportion  of  alkaline  salts,  which 
swell  up  as  the  tobacco  burns,  and  tear  the  fibres,  thereby  inducing 
complete  combustion.  Sulphates  rather  favour  proper  combination, 
while  nitrates  are  prejudicial.  Chlorides  are  regarded  by  most 
observers  as  objectionable,  and  hence  should  be  absent  from  fer- 
tilisers intended  for  application  to  tobacco  crops.^ 

A.  Mayer  (Land.  Versachs-Stat.,  xxxyui.  127;  Jour.  Chem. 
Soc,  Iviii.  1458)  has  investigated  the  influence  of  various  sub- 
stances employed  in  0'5  per  cent,  solution  on  the  combustibility  of 
ordinary  filter-paper.  Organic  substances  of  the  most  difi'erent 
kinds  were  found  favourable  to  combustion  with  flame  and  to 
diminish  the  power  of  glowing,  while  inorganic  substances  usually 
had  the  opposite  effect.^ 

From  his  experiments  with  filter-paper,  Mayer  concludes  that 
the  more  ash  tobacco  yields,  and  especially  the  more  potassium 
carbonate  (representing  organic  salts  of  potassium  in  the  tobacco), 
the  better  the  tobacco  will  burn ;  while  much  calcium  phosphate, 
sulphate,  or  chloride  is  held  to  be  prejudicial.  The  alkalinity  of 
the  ash  is  a  better  measure  of  combustibility  than  the  proportion 
of  chlorine.  Mayer  gives  the  following  figures  obtained  by  the 
partial  analysis  of  tobacco  of  difi'erent  qualities  from  Sumatra. 


Tobacco. 

Chlorine. 

Total 
Potash. 

Alkalinity 
as  K2CO3. 

ASH. 

Nitrogen. 

Good 

Sufficiently  good  Gight  \ 

ash),   ,       .               / 
Sufficiently  good, . 
Sufficiently  good  (grey  \ 

ash),    .       .        .        / 
Bad,       .        .       .       . 

1-5 
0-5 
0-7 
1-2 
8-8 

5-9 
5-8 
6-6 
7-9 
4-6 

4-9 
6-8 
5-5 
4-1 
0-5 

20-5 
20-8 
22-5 
17-7 
18-5 

2-7 
8-2 
2-0 
8-8 
2-6 

1  G.  Cantoni  {Bied.  Centr.,  1879,  p.  812)  found  that  nitrates  of  the 
dlkali-metals  had  most  effect  as  regarded  vigour  of  growth  of  the  tobacco,  while 
alkaline  chlorides  and  gypsum  were  prejudicial,  the  yield  in  weight  being 
actually  higher  when  no  manure  was  applied  than  when  ammonium  sulphate 
or  sodium  chloride  was  added.  The  leaf  was  almost  totally  incombustible 
when  the  plant  had  been  manured  with  gypsum,  but  that  produced  by  manur- 
*aig  with  potassium  sulphate  was  completely  combustible.  A.  Mayer  confirms 
the  statement  that  chlorides  are  objectionable  in  tobacco  manures,  and  states 
that  their  use  increases  the  proportion  of  chlorine  in  the  leaves  from  0*21  to 
0*52  per  cent. 

^  The  salts  found  most  favourable  for  glowing  were  the  alkaline  nitrates,  sul- 
phates, and  carbonates;  alkaline  organic  salts;  and  potassium  chloride.  Sodium 
salts  had  less  effect  than  potassium  salts,  and  calcium  and  magnesium  salts  much 
less  still.  Paper  treated  with  potassium  salts,  magnesium  sulphate,  or  sodium 
carbonate  gave  a  white  ash.     Chlorides  were  found  rather  to  favour  glowing. 


190 


COMPOSITION  OF  TOBACCO. 


According  to  J.  M.  van  Bemmelin  {Land.  Versuchs-Stat., 
xxxvii.  409;  Jour.  Chem.  Soc.^  Iviii.  1338),  tobacco  which  burns 
badly  either  contains  an  excess  of  chlorine  and  sulphuric  acid  over 
the  potash,  or  else  the  amount  of  potassium,  compared  with  that 
of  chlorine  and  sulphuric  acid,  is  low,  owing  to  the  potash  being 
partially  replaced  by  soda.  Leaves  of  the  best  quality  contain 
little  or  no  soda,  not  much  chlorine  or  sulphuric  acid,  but  a  large 
proportion  of  organic  salts  of  potassium,  calcium,  and  magnesium. 
Too  much  fat  or  albumin  in  the  tobacco  neutralises  the  good 
effect  of  organic  salts  of  potassium,  and  it  is  important  that  the 
albuminoids  and  carbohydrates  should  be  sufficiently  decomposed 
during  the  casing  of  the  tobacco.  In  the  ash  the  ratio  of 
COgrCl  +  SOg  is  not  less  than  7  : 1,  and  the  ratio  of  KiCl  +  SOg 
is  not  less  than  2:1. 

According  to  Mayer,  tobacco  which  burns  badly  can  be  made  to 
burn  well  by  steeping  it  for  twenty-four  hours  in  a  0'5  per  cent, 
of  potassium  acetate  or  nitrate.  Iti  this  way  soluble  organic  matter 
and  alkaline  chlorides  are  extracted,  while  the  salts  favourable  to 
glowing  are  taken  up.  By  steeping  in  a  0"5  per  cent,  solution  of 
calcium  acetate,  the  most  incombustible  tobacco,  which  can  other- 
wise only  be  used  for  snuff,  can  be  made  to  burn  well,  and  yield  a 
perfectly  white  ash. 

The  mode  of  existence  of  the  nitrogen  in  tobacco  has  been 
investigated  by  Fesca  and  Imai  (Jour.  Soc.  Chem.  Ind.,  vii. 
759),  who  have  published  the  following  among  other  interesting 
analytical  data  :  ^ — 


Highest 

Lowest 

Average 

Percentage. 

Percentage. 

of  S  Samples. 

In  air-dried  tobacco— 

Sand, 

1-91 

1-02 

1-48 

Moisture, 

12-21 

8-39 

10-46 

In  dry,  sand-free  tobacco— 

Pure  ash, 

14-64 

10-68 

12-82 

Containing  soluble  CO3,  . 
„        insoluble  CO2, 

0-57 

0-34 

0-44 

419 

3-05 

3-54 

„        K2O,       .... 

4-73 

3-14 

3-97 

Crude  fat, 

14-44 

10-34 

12-12 

1       Crude  fibre, 

15-50 

13-17 

14-10 

Total  nitrogen, 

1-69 

1-29 

1-44 

Amido-nitrogen,       .... 

0-67 

0-32 

0-48 

Albuminoids 

3-62 

0-69 

2-58 

Nicotine, 

4-09 

2-63 

3-16 

Per  \Q0  parts  of  total  nitrogen — 

N  as  amido-compounds, 

41-3 

23-2 

32-7 

2f  as  albuminoids,    .... 

40-0 

9-6 

29-2 

Nas  nicotine, 

48-6 

29-7 

38-1 

^  Fesca  and  Imai  deduce  the  following  conclusions  from  their  researches  : — 
The  quantity  of  nicotine  may  be  considered  as  bearing  the  same  relation  to 
tobacco  as  the  percentage  of  alcohol  does  to  spirituous  liquors  ;  but  as  yet  a 


COMBUSTIBILITY   OF   TOBACCO.  191 

The  aqueous  infusion  of  tobacco  contains  a  body  which  reduces 
F  e  h  1  i  n  g's  solution.  According  to  T.  J.  S  a  v  e  ry  (CJiem.  News, 
xlix.  123),  the  reducing  body  is  almost  entirely  precipitated  by 
basic  lead  acetate,  the  filtrate  being  without  action  on  Fehling's 
solution.  The  body  precipitated  by  lead  acetate  is  probably 
caffetannic  acid,  and  amounts,  according  to  J.  A 1 1  f  i  e  1  d 
(Pharm.  Jour.,  [3],  xiv.  541),  to  about  3  per  cent,  of  the  tobacco. 
But  Attfield  states  that  the  solution  after  treatment  with  basic 

high  percentage  of  nicotine  has  not  been  shown  to  be  an  indication  of  the 
good  quality  of  tobacco.  Nitric  acid  should  not  be  found  in  well -fermented 
tobaccos.  Ammonia  determinations  are  frequently  too  high,  as  they  include 
some  amido-nitrogen.  0"1  per  cent,  or  so  of  ammonia  does  not  seem  to  lower 
the  quality  of  the  tobacco.  The  albuminoids  in  a  tobacco  afford  no  indication 
of  quality  unless  the  proportion  of  amides  is  simultaneously  considered.  The 
amido-nitrogen  represents  for  the  most  part  harmless,  or,  perhaps,  even 
beneficial,  nitrogenous  compounds.  It  is  possible  that  a  further  study  of 
these  bodies  and  their  decompositions  will  reveal  the  presence  of  bodies 
exercising  a  direct  influence  on  the  quality  of  tobacco.  Anyway,  the  conver- 
sion of  albuminoids  into  amides  is  one  of  the  most  important  results  of  the 
fermentation.  Ordinary  fat  determinations,  or  rather  extracts,  are  of  no  use 
in  tobacco  analysis.  Carbohydrates  should  not  be  present  in  well-fermented 
tobacco,  but  a  study  of  the  changes  they  undergo  would  doubtless  be  of  great 
value  in  connection  with  tobacco.  Only  considerable  differences  in  the  amount 
of  the  various  constituents  of  tobacco  can  give  any  conclusive  indication  of  the 
quality  of  a  tobacco.  Very  bad  tobaccos  always  contain  much  albuminoid 
matter,  sulphuric  acid,  chlorine,  and  large  quantities  of  mineral  acids,  with 
small  proportions  of  amido-nitrogen,  potash,  &c.  By  the  present  methods  of 
analysis  it  is  easier  to  recognise  a  bad  tobacco  than  one  of  good  quality. 
Bases,  particularly  potash  and  lime,  in  medium  quantity,  are  favourable  to 
the  good  quality,  and  especially  the  combustibility,  of  tobacco.  An  excess  of 
either  of  these  bases  over  a  liberal  mean  percentage  is  neither  a  sign  of  good 
quality  nor  combustibility,  and  only  an  exceptionally  low  percentage  of  either 
of  them  can  be  regarded  with  certainty  as  a  bad  sign.  Very  high  magnesia  is 
prejudicial  to  the  combustibility.  Mineral  acids  in  large  quantities  indicate 
both  bad  combustibility  and  quality  ;  but  only  a  very  high  proportion  of  an 
individual  acid  can  be  safely  considered  a  decidedly  bad  indication.  The  com- 
bustibility is  influenced  to  the  greatest  extent  by  the  quantity  of  sulphuric  acid 
present,  and  in  a  diminishing  degree  by  the  percentage  of  chlorine,  phosphoric 
acid,  and  silica  in  the  tobacco.  The  percentage  of  soluble  carbonates  appears 
to  have  no  important  influence  on  the  quality  and  combustibility  of  tobacco  ; 
the  influence  of  the  total  quantity  of  carbonates  in  the  ash  is  much  greater, 
but  even  in  this  there  is  a  maximum  beyond  which  the  percentage  of  carbonic 
anhydride  in  the  ash  cannot  be  regarded  as  indicating  increase  of  combus- 
tibility. The  relation  of  carbonates  to  the  mineral  acids  is  a  much  more 
important  factor,  a  large  preponderance  of  the  former  being  a  favourable  sign. 
High  basicity  of  ash  is  an  excellent  indication  of  good  combustibility,  especially 
when  not  due  either  entirely,  or  to  a  great  extent,  to  magnesia  or  iron. 


192  TOBACCO   SMOKE. 

lead  acetate  still  contains  a  sugar-like  body,  which  he  did  not 
attempt  to  isolate,  and  which  had  little  or  no  optical  activity,  but 
which  yielded  alcohol  on  fermentation  with  yeast,  in  amount 
corresponding  to  an  average  of  7  per  cent,  of  sugar.  Eastes 
and  Ince  (Pharm.  Jour.,  [3],  xvi.  682)  found  a  small  percentage 
(2 "5  to  5 "3)  of  a  fermentable  saccharoid  matter,  not  removable  by 
lead  acetate,  in  the  extract  of  tumbeki  or  Persian  tobacco 
{Nicotiana  Persica).  The  nicotine  in  this  product  ranges  from 
2  to  nearly  6  per  cent.,  and  the  ash  from  22  to  28  per  cent. 

H.  Miiller  (Bied.  Gentr.,  1886,  p.  409  ;  Jour.  Chem.  Soc,  1. 
904)  states  that  fermented  tobacco  contains,  as  a  rule,  little  or  no 
starch,  and  no  sugar.  The  whole  of  the  starch  commonly  disap- 
pears during  the  first  few  days  of  the  drying.  The  sugar  thus 
formed  is  often  converted  into  water  and  carbon  dioxide,  and  this 
change  seems  to  be  complete  in  leaves  quickly  dried.  The  last 
trace  of  sugar  disappears  when  fermentation  sets  in,  while  any 
residual  starch  does  not  appear  to  be  altered. 

From  the  analyses  already  quoted,  it  is  evident  that  the  propor- 
tion of  nicotine  in  tobacco  varies  considerably.^  According  to 
Schloesing  (Chem.  Gazette,  v.  43)  dried  French  tobacco  con- 
tains from  5  to  8  per  cent,  of  the  alkaloid  ;  Virginia  and  Kentucky, 
6  to  7  per  cent. ;  while  Maryland  and  Havana  tobaccos  contain 
only  about  2  per  cent.,  and  ordinary  snuff  about  the  same  propor- 
tion. L.  Eicciardi  (Ber.,  xi.  1385)  to  some  extent  confirms 
these  results,  for  he  found  the  nicotine  in  twenty  specimens  of 
tobacco,  grown  in  Italy  under  various  conditions,  to  range  from 
5*99  per  cent,  in  a  Virginian  variety  to  1*62  in  Havana  tobacco. 

Tobacco  Smoke  varies  in  character  according  to  the  proportion  of 
air  admitted  during  combustion,  oxidation  being  necessarily  more 
perfect  in  the  case  of  a  cigar  than  when  the  tobacco  is  smoked  in 
a  pipe.  In  the  latter  case,  a  portion  of  the  condensible  products 
is  deposited  in  the  liquid  state.  Tobacco- smoke  consists  in  part  of 
permanent  gases,  the  proportions  of  carbon  dioxide  and  carbon  mon- 
oxide in  which  have  been  determined  by  G.  Krause.  Vohl 
found  sulphuretted  hydrogen  and  hydrocyanic  acid,  and  from  0*7  to 
2*8  grammes  of  ammonia  for  100  of  tobacco  smoked.  Vohl  and 
Eulenberg  {Arch.  Pharm.,  [2],  cxlvi.  130)  experimented  on 
the  smoke  of  strong  tobacco,  burnt  both  in  pipes  and  in  the  form 
of  cigars.     The  smoke  was  first  aspirated  through  a  solution  of 

1  According  to  Ad.  Mayer  a  liberal  amount  of  heat  and  liglit,  together 
with  sufficient  moisture  in  a  rich  soil,  will  not  only  cause  a  luxurious  develop- 
ment of  tobacco  plants,  but  give  a  large  increase  in  the  percentage  of  nicotine, 
while  the  other  organic  constituents  of  the  plant  are  not  much  affected  by 
climatic  conditions. 


TOBACCO  EXTRACT. 


193 


caustic  potash,  and  then  through  dilute  sulphuric  acid.  The  alhali 
absorbed  carbon  dioxide,  sulphuretted  hydrogen,  hydrocyanic, 
formic,  acetic,  propionic,  butyric  and  valeric  acids,  phenol  and 
creosote ;  the  presence  of  caproic,  caprillic,  and  succinic  acids  could 
not  be  ascertained  conclusively.  The  acid  absorbed  ammonia, 
pyridine,  CgHg]^,  and  all  the  homologues  of  the  series  to  viridine, 
CjgHjgN,  inclusive.  In  addition  to  the  above,  carbon  monoxide, 
methane,  and  several  hydrocarbons  of  the  acetylene  series  were 
detected.  Pyridine  was  the  chief  base  in  the  smoke  from  pipes, 
while  coUidine  was  the  prominent  base  in  cigar-smoke. 

V o h  1  and  Eulenberg  conclude  that  the  nicotine  of  tobacco 
is  completely  decomposed  during  the  process  of  smoking,  and  that 
the  intense  action  of  tobacco-smoke  on  the  nervous  system  is  due 
to  the  presence  of  bases  of  the  pyridine  series.  There  is  no  doubt 
that  some  observers  have  mistaken  these  bases  for  nicotine ;  but 
M  e  1  s  e  n  s'  experiments  {Dingl.  Polyt.  Jour.,  xlvii.  212)  appear  to 
be  conclusive  as  to  the  presence  of  nicotine,  which  he  isolated  in 
a  condition  fit  for  analysis  and  to  the  amount  of  about  33 
grammes  for  4J  kiligrammes  of  tobacco  smoked,  or  about  one- 
seventh  of  the  quantity  originally  present.^ 

Tobacco  Extract  varies  greatly  in  strength,  and  should  always 
be  assayed  for  the  proportion  of  nicotine.  A  good  extract  is  said  to 
contain  about  7  per  cent,  of  the  alkaloid.  The  following  analyses 
by  E.  Geissler  {Jour.  Soc.  Chem.  Ind.,  viii.  425),  of  tobacco 
extract  of  40°  Baum^,  indicate  a  wide  difi'erence  in  its  character, 
according  as  it  is  prepared  from  the  leaves  or  midribs  of  the 
tobacco. 


Liquid. 

Mineral 
Matter. 

Containing 
K2CO3 

Organic 
Matter. 

Containing 
Nicotine. 

Extract  from  leaves,    . 
Extract  from  midribs, . 

36-2 

32-8 

15-5 
22-1 

5-0 

7-73 

50-86 
48-40 

8-1 
1-86 

Snuff  is  manufactured  from  refuse-tobacco,  such  as  stems,  tobacco- 
smalls,  and  sweepings.  These  are  moistened  with  water,  subjected 
to  a  process  of  fermentation  during  six  or  eight  weeks,  then  ground, 
mixed  with  alkaline  salts  as  preservatives,  and  flavoured  as  desired. 
In  the  United  Kingdom,  nothing  is  allowed  to  be  added  to  snuff 

^  Melsens'  conclusion  has  been  endorsed  by  R.  K i s s  1  i n g  {Ding.  Polyt. 
Jour.,  ccxliv.  64),  who  has  collected  and  reviewed  the  observations  of  previous 
investigators.  He  considers  V  o  h  1 '  s  conclusion  as  to  the  non-existence  of 
nicotine  in  tobacco-smoke  to  be  due  to  that  chemist  having  overlooked  the 
fact  that  the  alkaloid  is  decomposed  by  warm  caustic  potash,  a  reaction  which, 
if  a  fact,  has  certainly  not  met  with  general  recognition. 

VOL.  III.  PART  II.  N 


194  SNUFF — PITURINE. 

but  the  chlorides,  sulphates,  and  carbonates  of  potassium  and 
sodium,  and  the  carbonate  of  ammonium;  and  any  snuff  which 
contains  a  greater  proportion  of  these  salts  than  26  per  cent,  on 
the  dry  snuff,  including  the  salts  natural  to  the  tobacco,  is  liable  to 
forfeiture  and  a  penalty  of  £50.  As  the  proportion  of  alkaline 
salts  in  tobacco-ash  varies  considerably,  it  is  important  that  the 
manufacturer  should  know  the  amount  present,  in  order  that  he 
may  compound  a  snuff  of  uniform  composition,  and  not  exceed  the 
legal  limit.  Of  the  salts  allowed  to  be  added  to  snuff,  common 
salt  and  the  carbonates  of  potassium  and  ammonium  are  those  most 
commonly  used.  In  addition,  most  snuff  contains  from  25  to  45 
per  cent,  of  water,  and  sometimes  a  considerable  quantity  of  sand, 
the  proportion,  according  to  J.  Clark  {Jour.  Soe.  Ohem.  Ind., 
iii.  554),  averaging  5  per  cent,  on  the  dry  snuff;  but  ranging  from 
0'5  to  over  10  per  cent.,  and  in  one  case  exceeding  30  per  cent. 
A  large  number  of  gross  and  more  or  less  apocryphal  adulterants 
of  snuff  have  been  recorded.  Among  these  the  sulphides  of  arsenic, 
mercury  and  antimony,  chromate  of  lead,  bichromate  of  potassium, 
sulphates  of  copper  and  iron,  alum,  lamp-black,  ivory-black,  cream 
of  tartar,  red  ochre,  brick-dust,  and  various  organic  matters  find  a 
place.  As  snuff  is  neither  a  "  drug "  nor  an  article  of  food,  it  is 
not  liable  to  examination  under  the  Adulteration  Acts,  and  the 
Excise  systematically  ignore  sophistications  which  do  not  affect  the 
revenue.  Hence,  authentic  information  respecting  the  present 
adulterations  of  snuff  is  very  limited. 

Piturine.    CigH^gNg. 

Piturine,  the  volatile  alkaloid  of  pituri,^  was  regarded  by 
Petit  as  identical  with  nicotine,  but  its  distinct  individuality  has 
been  established  by  Liversidge  {Pharm.  Jour.,  [3],  xi.  815). 

In  its  chemical  characters  and  physiological  effects  piturine 
presents  the  closest  resemblance  to  nicotine,  but  is  distinguished 
from  that  base  by  its  reaction  with  Palm's  test.  When  gently 
warmed  with  hydrochloric  acid  of  1'12  specific  gravity,  nicotine 
turns  violet,  and  on  addition  of  a  little  strong  nitric  acid  the  colour 
changes  to  a  deep  orange.  Piturine  whW  thus  treated  does  not 
change  colour  at  all,  but  when  further  heat  is  applied  it  turns  yellow. 

Piturine  is  distinguished  from  c  o  n  i  n  e  by  its  aqueous  solution 
not  becoming  turbid  on  heating,  or  by  the  addition  of  chlorine- 
water  ;  from  aniline  it  is  distinguished  by  its  negative  reaction 
with  solution  of  bleaching  powder  ;  and  from  picoline  by  being 
somewhat  denser  than  water.     From  pyridine,  piturine  differs  by 

^  Pituri  consists  of  the  dried  leaves  of  Duboisia  Eopwoodii,  a  shrub  growing 
in  Australia.     It  contains  from  1  to  2^  per  cent,  of  the  alkaloid. 


LOBELINE.  195 

giving  a  precipitate  with  cupric    sulphate  insoluble  in  excess  of 
the  base. 

When  piturine  is  treated  in  ethereal  solution  with  iodine  (com- 
pare sparteine)  the  liquid  becomes  brownish  red  and  turbid,  and 
after  a  short  time  deposits  yellowish  red  needles,  leaving  a  yellow 
mother-liquor.  The  crystals  melt  at  about  110°  C,  and  dissolve 
in  alcohol  with  brownish  red  colour.  This  solution  leaves  indis- 
tinct needles  and  oily  drops  on  evaporation ;  if  treated  in  the  cold 
with  caustic  soda,  an  iodoform-like  odour  is  evolved ;  whereas  the 
iodine-compound  of  nicotine  is  said  to  reproduce  nicotine  when 
similarly  treated. 

Lobeline  is  the  active  principle  of  Lobelia  inflata,  or  Indian 
tobacco,  a  plant  which  has  received  extensive  application  by  un- 
authorised practitioners,  and  is  also  an  official  drug.^ 

Lobeline  exists  in  lobelia  in  combination  with  a  vegetable  acid. 
In  presence  of  certain  other  constituents  of  the  plant  the  alkaloid 
is  extremely  unstable,  being  rapidly  decomposed  on  heating  an 
aqueous,  or  even  an  alcoholic,  infusion  of  lobelia.  In  presence  of 
acetic  acid  the  base  is  more  stable,  and  was  obtained  by  J.  W. 
and  C.  G.  Lloyd  {Pliarm.  Jour.,  [3],  xvii.  1038;  xviii.  135) 
as  a  colourless,  odourless,  amorphous  substance,  permanent  in  the 
air,  only  slightly  soluble  in  water,  but  readily  soluble  in  alcohol, 
ether,  chloroform,  benzene,  carbon  disulphide,  &c.  In  the  pure 
state  lobeline  is  not  hygroscopic,  and  is  but  slowly  changed  on 
exposure  to  air.  Lobeline  turns  red  with  sulphuric  acid,  yellow 
with  nitric  acid,  and  is  precipitated  by  all  the  general  alkaloidal 
reagents.  The  salts,  which  have  not  been  obtained  crystallised,  are 
readily  soluble  in  water,  alcohol,  and  ether.  They  are  described 
as  most  violent  emetics,  a  single  drop  of  a  tolerably  strong  solution 
producing  immediate  emesis,  without  disagreeable  after-symptoms. 
The  dust  is  as  irritating  as  veratrine  to  the  nose  and  air-passages. 

^  The  entire  dried  herb  constitutes  the  official  drug,  but  the  dried  seeds 
of  lobelia  are  also  largely  used.  The  root  of  Lobelia  syphilitica  was  employed 
before  L.  inflata  was  known  to  medicine,  but  the  root  of  the  latter  species  does 
not  appear  to  have  been  used.  According  to  J.  W.  and  C.  G,  Lloyd,  all 
parts  of  lobelia  contain  the  alkaloid,  which,  however,  is  most  readily  obtained 
from  the  seeds. 

The  dust  of  the  plant  produces  a  painful  sensation  when  inhaled.  All  parts 
of  the  herb  and  seed  produce  an  acrid  biting  sensation  on  the  tongue,  and  a 
sharp,  tobacco-like  impression  on  the  throat  and  fauces.  Lobelia  contracts 
the  pupil,  and  acts  as  an  expectorant  in  small  doses  and  an  emetic  in  larger 
(10  to  20  grains).  In  poisonous  quantities  it  acts  like  nicotine,  and  kills  by 
paralysing  the  respiration.  Several  fatal  cases  of  poisoning  by  lobelia  are  on 
record. 


196  LOBELINE. 

Inflatin  was  obtained  by  J.  W.  and  C.  G.  Lloyd  in  large 
colourless,  odourless  crystals,  melting  at  225°,  insoluble  in  water 
or  glycerin,  but  soluble  in  alcohol,  ether,  chloroform,  benzene, 
carbon  disulphide,  and  the  oil  of  lobelia,  &c.  Inflatin  is  a  neutral 
principle,  and  appears  to  have  no  therapeutic  value.  The  lolelacrin 
of  E  n  d  e  r  s  is  considered  by  the  Lloyds  to  be  a  mixture  of 
inflatin,  resin,  lobeline,  and  the  fixed  oil  which  lobelia  contains  in 
the  proportion  of  about  30  per  cent. 

No  liquid  volatile  alkaloid  could  be  obtained  by  Messrs  Lloyd 
from  lobelia,  by  distilling  the  herb  with  water,  either  with  or  with- 
out the  addition  of  caustic  alkali,  and  they  considered  the  supposed 
volatile  base  to  have  been  probably  a  mixture  of  lobeline,  inflatin, 
and  volatile  oil. 

On  the  other  hand,  Paschkis  and  Smita  {Monatsh.,  xi. 
131;  Jour.  Soc.  Ghem.  Ind.,  ix.  761)  have  obtained  a  volatile 
alkaloid  from  Lobelia  injiata^  by  extracting  the  leaves  with  water 
acidulated  with  acetic  acid,  rendering  the  concentrated  solution 
alkaline,  and  agitating  with  ether.  On  distilling  ofi"  the  solvent 
the  alkaloid  is  obtained  as  a  viscous  oil,  with  an  odour  at  once 
resembling  that  of  honey  and  tobacco.  It  is  purified  by  solution 
in  dilute  hydrochloric  acid,  and  re-extracted  by  alkali  and  ether.^ 
After  distilling  off  the  ether  the  base  is  dried  with  caustic  potash, 
and  distilled  in  a  current  of  hydrogen.  On  warming  the  alkaloid 
so  obtained  with  a  10  per  cent,  solution  of  caustic  potash,  and 
gradually  adding  a  4  per  cent,  aqueous  solution  of  potassium 
permanganate,  benzoic  acid  is  formed,  and  can  be  extracted  by 
filtering  off  the  precipitated  oxide  of  manganese,  and  agitating 
the  acidulated  solution  with  ether. 

The  sulphate  of  the  above  volatile  alkaloid,  if  prepared  from 
lobelia  seeds,  is  obtained  in  yellow,  very  hygroscopic  granules. 
When  prepared  from  the  leaves,  it  forms  a  yellowish  white  powder, 
less  hygroscopic  than  the  salt  from  the  former  source. 

According  to  D  r  e  s  e  r,  lobeline  is  the  only  medicinally  active 
principle  contained  in  Lobelia  inflata.  S.  Nunez  {Brit.  Med. 
Jour.y  1889,  1059)  considers  it  gre^y  superior  to  the  galenical 
preparations  of  lobelia,  and  recommends  it  in  the  treatment  of 
spasmodical  asthma  and  bronchitical  dyspnoea. 


^  Up  to  this  point  the  process  of  Paschkis  and  Smita  is  substantially  the 
same  as  that  of  the  Lloyd  Bros,  for  the  preparation  of  the  non-volatile  alkaloid 
of  lobelia.  S  i  e  b  e  r  t,  by  the  same  process,  has  recently  obtained,  both  from 
the  herb  and  seeds  of  lobelia,  a  pale  yellow  alkaline  syrup,  the  crystallised 
hydrochloride  and  chloroplatinate  of  which  indicated  the  formula  CigHgaNOg 
for  the  free  alkaloid. 


SPARTEINE.  197 

Sparteine.    CigHggiS  ^. 

This  alkaloid  is  obtained  by  H  o  u  d  ^  and  L  a  b  o  r  d  e  (Pharm. 
Jour.,  [3],  xvi.  543)  by  exhausting  in  a  displacement-apparatus 
with  proof-spirit  the  coarsely-powdered  leaves  and  branches  of 
broom  (Spartium  scoparium).  The  product  is  filtered,  distilled 
under  reduced  pressure,  the  residue  dissolved  in  tartaric  acid,  the 
liquid  filtered  to  remove  a  greenish  deposit  containing  chlorophyll 
and  scoparin,  CgiHggOj^Q,  the  filtrate  rendered  alkaline  by  potas- 
sium carbonate,  and  agitated  several  times  with  ether.  The 
ethereal  solution  is  shaken  with  tartaric  acid,  and  the  acid  liquid 
separated  and  again  rendered  alkaline  and  extracted  with  ether, 
which  on  evaporation  leaves  the  alkaloid ;  the  yield  being  about 
0'3  per  cent,  of  the  plant  used. 

Sparteine  is  a  colourless,  oily  liquid,  boiling  at  287°  at  the  ordi- 
nary pressure,  or  at  180°  at  20  mm.  It  has  a  somewhat  pungent, 
pyridine-like  odour,  a  very  bitter  taste,  and  on  exposure  to  air  turns 
brown  and  thick.  It  is  soluble  in  alcohol,  ether,  and  chloroform, 
but  insoluble  in  petroleum  ether.  Its  solution  in  alcohol  (24  per 
cent.)  has  a  specific  rotation  of  —  14°*6  for  the  sodium  ray. 

Sparteine  is  a  well-defined  base,  uniting  with  acids  to  form 
crystallisable  salts,  and  having  the  constitution  of  a  tertiary 
diamine.  The  sulphate  forms  large,  transparent,  very  soluble 
rhombohedra,^  a  solution  of  which  gives  with  caustic  alkalies  and 
ammonia  a  white  precipitate  insoluble  in  excess.  Cadmium  iodide 
gives  a  white  curdy  precipitate,  and  sodium  phosphomolybdate  a 
white  precipitate,  dissolving  on  heating  the  liquid.  Platinum 
chloride  yields  a  yellow  precipitate  of  BH2FtCl6-j-2aq.,  very 
insoluble  in  cold  water  and  alcohol,  but  crystallising  from  hydro- 
chloric acid  in  rhombic  prisms.  Sparteine  gives  no  coloration 
with  concentrated  mineral  acids. 

"When  oxidised  with  potassium  permanganate,  sparteine  yields  a 

^  Administered  in  doses  of  0"1  gramme,  Sparteine  sulphate  is  stated  (G.  See, 
Compt.  Rend.,  ci.  1046  ;  Year-Bodk  Pharm.,  1886,  p.  283)  to  have  a  tonic  action 
on  the  heart  more  prompt  and  lasting  than  that  of  digitalis  or  convallamarin, 
restoring  the  rhythm  of  the  heart's  action  better  than  any  known  remedy, 
and  resembling  belladonna  in  accelerating  the  heart-beats  in  weak  and  atonic 
conditions  of  the  heart.  It  does  not  appear  to  have  any  injurious  action  on 
the  digestion,  or  on  the  nervous  system  generally. 

According  to  De  Rymon,  sparteine  causes  tremor,  dilation  of  the  pupils, 
inco-ordiuation  of  movements,  and  convulsions  alternately  tonic  and  clonic. 

Schroff  found  that  a  drop  of  sparteine  introduced  into  a  rabbit's  mouth 
occasioned  spasms  of  the  muscles  of  the  spine  and  limbs  and  paralysis  of  the 
latter,  slowing  of  the  respiration  and  heart,  and  death  in  six  minutes. 

The  effects  of  sparteine  have  been  compared  to  those  of  conine,  but  they  do 
not  explain  the  value  of  broom  as  a  diuretic  medicine. 


198  SPIGELINE. 

small  quantity  of  a  volatile  (apparently  fatty)  acid,  together 
with  a  non-volatile  py ridine-carboxy lie  acid,  which  on 
distillation  with  lime  yields  pyridine.  Heated  in  sealed  tubes 
with  fuming  hydriodic  acid,  sparteine  yields  methyl  iodide 
and  abase  containing  Cj^Hg^Ng. 

According  to  B  e  r  n  h  e  i  m  e  r,  on  gradually  adding  3  parts  of 
iodine  dissolved  in  ether  to  an  ethereal  solution  of  1  part  of 
sparteine  a  black  precipitate  is  formed,  which,  when  separated, 
washed  with  ether,  and  dissolved  in  boiling  alcohol,  crystallises 
on  cooling  in  beautiful  green  needles  containing  CigHggNg-'-s- 
This  body  is  insoluble  in  cold  water  or  alcohol,  but  dissolves 
in  either  liquid  when  heated.  It  is  insoluble  in  ether,  permanent 
in  the  air,  and  yields  free  sparteine  when  heated  with  caustic 
alkali  (compare  "Piturine,"  page  195).  Bromine  acts  strongly  on 
sparteine  at  the  ordinary  temperature,  even  when  largely  diluted 
with  ether,  forming  an  undefined  resinous  mass. 

According  to  Grandval  and  V a  1  s e r,  when  a  drop  of  ammo- 
nium sulphydrate  is  placed  on  a  watch-glass,  and  a  trace  of  spar- 
teine or  one  of  its  salts  added  to  it,  a  permanent  orange-red  colora- 
tion is  immediately  produced. 

Spigeline  is  the  active  principle  of  Spigelia  Marylandicay 
or  "pink-root."  As  obtained  by  W.  L.  Dudley  by  distil- 
ling the  root  with  milk  of  lime  it  was  volatile,  gave  with  iodine 
a  brownish-red  precipitate,  and  with  Mayer's  reagent  a  white 
crystalline  precipitate  soluble  in  alcohol  and  ether,  and  differing 
from  most  similar  precipitates  by  being  soluble  in  dilute  acid. 
Spigeline  is  said  by  S  t  a  b  1  e  r  to  be  bitter,  precipitated  by  tannin, 
and  soluble  in  water  and  alcohol,  but  not  in  ether  (?).  Pink-root 
is  often  used  as  a  vermifuge,  and  possesses  poisonous  properties 
allied  to  those  of  gelsemium,  depressing  the  action  of  the  heart 
and  of  respiration,  and  in  large  doses  causing  loss  of  muscular 
power  {Practitioner,  July  1887;  Amer.  Chem.  Jour.,  i.  138).  It 
produces  strabismus,  dilatation  of  the  pupils,  and  temporary  loss 
of  sight,  with  some  drowsiness  but  not  narcotism.  A  fluid  extract 
of  spigelia  root  is  official  in  the  U.S.  Pharmacopoeia. 


ACONITE  BASES.^ 

The  different  species  of  Aconitum  contain  alkaloids  of  a  closely- 
allied  character,  but  which  differ  from  each  other  in  their  chemical 

1  The  subjects  of  this  section  are  discussed  at  greater  length  and  in  more 
detail  than  their  intrinsic  importance  seems  to  warrant,  but  it  appears  desir- 


ACONITE   PLANTS.  199 

composition  and  physiological  activity.  The  characteristic  aconite 
alkaloids  are  perhaps  the  most  violent  poisons  known,  but  certain 
species  of  aconite  contain  simply  harmless,  bitter  principles.  All 
parts  of  the  plant  contain  the  poison,  but  the  root  is  richest  in 
alkaloid.  If  any  portion  of  a  poisonous  aconite  plant  be  chewed, 
it  will  be  found  to  have  a  taste  which  may  be  at  first  bitterish 
sweet,  but  after  a  time  becomes  acrid  and  burning,  causing  a 
persistent  sense  of  tingling  and  numbness  of  the  gums  and  tongue, 
which  effect  lasts  for  some  time  and  is  highly  characteristic. 

For  medicinal  use,  the  German  and  United  States 
Pharmacopoeias  admit  only  the  tuberous  root  of  Aconitum 
Napellus (W olf's-bane  or  Monk's-hoo d).^  The  extract 
of  aconite  of  the  British  Pharmacopoeia  is  prepared  from 
the  fresh  leaves  and  flowering  tops  of  A.  Napellus  ("  gathered  when 
about  one-third  of  the  flowers  are  expanded,  from  plants  cultivated 
in  Great  Britain"),  while  the  alkaloid  (the  description  of  which 
points  to  an  impure  product),  the  liniment  and  the  tincture 
are  directed  to  be  prepared  from  the  carefully-dried  root  of  the 
same  plant  ("  collected  in  winter  or  early  spring  before  the  leaves 
have  appeared,  from  plants  cultivated  in  Britain  or  imported  in  a 
dried  state  from  Germany  ").2  The  French  Codex  authorises  the 
use  of  the  leaf  and  root  of  both  A.  Napellus  and  A.  ferox  possibly 

able  to  present  the  chemistry  of  the  aconite  bases  in  a  more  complete  form 
than  has  been  done  since  the  publication  of  Alder  Wright's  classical 
researches  ending  in  1880.  The  author  is  indebted  to  Dr  C.  E.  Alder  Wright 
for  perusal  and  correction  of  the  article. 

^  The  root  of  A.  Napellus  is  from  2  to  4  inches  long,  and  of  an  irregu- 
lar conical  form.  It  is  much  shrivelled  longitudinally,  and  is  more  or  less 
covered  with  the  scars  and  bases  of  broken  rootlets.  Externally  it  is  coffee- 
brown,  but  the  transverse  section  is  whitish,  and  exhibits  a  central  cellular 
axis  with  about  seven  rays.  The  freshly-cut  section  rapidly  acquires  a  reddish 
tint,  a  character  which  distinguishes  aconite  root  from  horse-radish,  which  it 
remotely  resembles,  and  for  which  it  has  been  fatally  mistaken.  The  details  of 
the  structure  of  aconite  root  have  been  minutely  described  by  Richards  and 
Rogers  {Pharm.  Joicr.,  [3],  xix.  912;  Chemist  aind  Druggist,  May  18,  1889), 
who  point  out  certain  differences  between  the  German  and  British  grown  roots. 
The  structure  of  A.  heterophylluvi  and  Japanese  aconite  have  been  described 
minutely  byWasowicz  {Pharm.  Jour.,  [3],  x.  301;  xi.  149). 

2  Notwithstanding  the  importance,  in  the  case  of  such  a  drug  as  aconite,  of 
adhering  strictly  to  the  directions  of  the  Pharmacopoeia,  it  is  stated  on 
the  high  authority  of  E.  M.  Holmes  {Pharm.  Jour.,  [3],  xx.  900)  that 
aconite-root  as  met  with  in  commerce  is  generally  of  German  or  Japanese 
origin,  the  former  being  gathered  indiscriminately  from  plants  which  may  vary 
as  widely  in  properties  as  A.  heterophyllum  (non-poisonous)  and  A.  ferox 
(highly  poisonous),  and  certainly  do  vary  as  much  as  A.  Napellus  (intensely 
poisonous)  and  A.  paniculatum  (non-poisonous). 


200  ACONITE   ROOTS. 

owing  to  the  widely-spread,  but  apparently  mistaken,  impression 
that  the  alkaloid  known  as  Morson's  aconitine  is  prepared  from 
the  latter  species  (compare  foot-note  on  page  216). 

The  roots  of  aconite  plants  are  not  only  the  richest  in  total 
alkaloidal  contents,  but  the  alkaloids  extracted  from  the  root  of  A. 
Napellus  were  found  by  C.  R.  Alder  Wright  to  contain  a  much 
larger  proportion  of  the  crystalline  base  aconitine  than  the  alka- 
loids from  the  other  parts  of  the  plant  (stem,  leaves,  and  flowers). 

The  various  natural  alkaloids  of  the  aconites  are,  broadly  speaking, 
characteristic  of  particular  species  of  the  plant.  Thus  aconitine 
is  the  peculiar  alkaloid  of  A.  Napellus,  pseudaconitine  of 
A.ferox,  and  japaconitine  of^.  Fischeri.  It  is  highly  probable 
that  the  traces  of  pseudaconine  found  by  Alder  Wright  in  the 
alkaloids  from  A.  Napellus,  and,  conversely,  the  trace  of  aconitine 
detected  in  the  bases  from  A.  ferox,  were  due  to  unsuspected 
admixtures  of  other  species  of  aconite  in  the  parcels  of  roots 
which  professedly  came  from  one  species  only.-^  Thus,  twenty-nine 
varieties  of  A.  Napellus  have  been  described,  and  some  of  these 
exhibited  such  differences  that  only  an  expert  could  distinguish 
them  from  nearly  allied  species.  The  true  A.  Napellus  flowers  in 
May,  and  appears  to  be  peculiar  in  this  respect ;  it  is  impossible 
even  for  a  skilled  botanist  to  distinguish  the  plant  by  its  leaves 
alone  (E.  M.  Holmes,  Pharm.  Jour.,  [3],  xii.  736).2 

The  roots  of  at  least  two  species  of  Japanese  aconite  occur  in 
the  United  States,  viz.,  Aconitum  Fischeri  and  A.  uncinatum.  The 
latter  species  has  been  described  as  poisonous ;  but,  according  to 
V.  Coblentz,  the  root,  although  it  contains  an  alkaloid,  is 
entirely  devoid  of  the  tingling  and  numbing  taste  of  A.  Napellus. 
The  physiological  experiments  of  Bartholow  on  the  root  of 
A.  Fischeri  indicate  that  this  plant  increases  the  number  and  force 
of  the  cardiac  pulsations,  instead  of  reducing  the  heart's  action  like 
A.  Napellus.  These  and  other  results  show  that  japaconitine  and 
preparations  of  the  Japanese  root  should  by  no  means  be  substituted 
for  A.  Napellus  for  internal  administration  {Pharm.  Jour.,  [3],  xvi. 
645). 

Besides  the  eminently  poisonous  alkaloids,  aconitine,  pseud- 
acofnitine  and  japaconitine,  characteristic  respectively  of  Aconitum 
Napellus,   A.  ferox,    and    A.  Fischeri,    other    species    of    aconite 

^Mandelin,  by  the  examination  oiA.  Napellus  alkaloids  of  various  degrees 
of  purity,  was  not  able  to  detect  pseudaconitine ;  and  J  ii  r  g  e  n  s  also  failed. 

*  The  root  of  Imperatoria  Ostruthium,  ormasterwort,  has  been  met  with 
as  an  adulterant  of  aconite.  It  resembles  aconite  tubers  in  shape,  but  has  an 
aromatic  odour  and  pungent  taste,  and  the  transverse  section  exhibits  numerous 
oil  cells  arranged  in  several  circles. 


ACONITE   SPECIES. 


201 


contain  alkaloids  which  appear  in  some  cases  to  be  highly  poison- 
ous, and  in  other  cases  harmless,  bitter  tonics.  Thus  the  alkaloid 
of  Aconitum  paniculatum  (which  was  the  official  aconite  of  the 
London  and  Dublin  Pharmacopoeias  of  1836)  is  an  inert,  bitter 
principle,  not  improbably  identical  with  the  picraconitine  isolated 
by  T.  B.  Groves  from  a  parcel  of  roots  supposed  to  be  those 
of  A.  Napellus.  The  root  of  A.  heterophyllum  contains  a  non- 
poisonous  bitter  alkaloid,  called  by  its  discoverer  atisine ;  and  it 
is  probable  that  similar  bases  occur  in  other  species.  Lyaconitine 
and  myoctonine  are  physiologically  active  alkaloids  isolated  from 
A.  lycoctonum.  Some  species  of  aconite  appear  to  contain  an 
unisolated  base  having  distinct  narcotic  properties. 

The  following  table  shows  the  chief  sources  of  the  aconite 
alkaloids  and  their  derived  bases.  The  root  is  the  part  of  the 
plant  referred  to  in  each  case  : — 


Plant. 

Saponiflable  Bases. 

Basic  Products  of 
Saponification. 

1 
Unsaponifiable 
Alkaloids. 

Aconitum  Napellus. 
Monk's-hood.        Wolfs- 
bane (blue  flowers). 

Aconitum  Ferox. 
Indian  aconite.     Nepaul 
aconite.  Himalaya  root. 
"Bikh"  or  "Bish." 

Aconitum  Anthora  (yellow- 
ish or  white  flowers). 

Aconitum  Fischeri. 
Japanese  aconite. 

Aconitum  Undnatum. 

Aconitum  Paniculatum. 

Aconitum  Lycoctonum  (yel- 
low flowers). 

Aconitum    Heterophyllum 
(blue     or    dirty    yellow 
flowers,with  purple  veins). 
Atis  or  Atees  root. 

Aconitine. 

Amorphous  base. 

Picraconitine  (ex- 
ceptionally pre- 
sent). 

Pseudaconitine  (very 
small  quantity,  if 
at  all). 

Pseudaconitine. 
Amorphous  base  (?). 
Aconitine    (in   very 

small  quantity,  if 

at  all). 

Pseudaconitine  (?). 

Japaconitine. 
Amorphous  base  (?). 

Bitter  inactive  alka- 
loid. 
Picraconitine  (?). 

Lyaconitine. 

Myoctonine. 

? 

Aconine. 

? 

Picraconine. 

Pseudaconine. 

Pseud  aconine. 
Aconine. 

Pseudaconine. 

Japaconine. 
? 

? 

Picraconine  (?). 

Lyaconine  (Lycocto- 

nine). 
Lyaconine  (Lycocto- 

nine). 

Amorphous  unnamed 
base. 

Amorphous  unnamed 
base. 

Amorphous  unnamed 
base. 

Atisine. 

Constitution   and   Characters    of   the   Aconite 
Bases. 

Much  of  the  earlier  work  on  the  alkaloids  of  the  aconites  is 
of    little    value,   owing    to    the    readiness  with  which    the    bases 


202 


CONSTITUTION  OF  ACONITE   BASES. 


undergo  decomposition,  and  the  consequent  failure  of  the  observers 
to  obtain  them  in  a  pure  state. 

The  following  table  shows  the  leading  properties  of  the  better 
known  of  the  aconite  bases. 


Name. 

Synonyms  and 
Sources. 

Formula. 

Appearance  and 
Characters. 

Physiological 

Aconitine, 

Napaconitine. 

C33H48NO12 

188 

Crystallisable  both  in 

Intensely 

Crystallised 

free    state    and    as 

poisonous. 

aconitine. 

salts.    Alkaloid  dex- 

From        A. 

tro-rotatory.       Salts 

Napellus. 

laevo-rotatory. 

Anhydro-aconi- 

Apoaconitine. 

C33H43NOU 

186 

Small   coherent    crys- 

As    poisonous 

tine, 

tals  ;          crystalline 
salts. 

as  aconitine. 

Aconine,  . 

Saponification 

C26H41NOU 

130 

Amorphous ;        forms 

Bitter ;  moder- 

of aconitine. 

amorphous  salts.  Re- 
duces Fehling's  solu- 
tion. 

ately  poison- 
ous. 

Paeudaconltine, 

Acraconitine ; 

C36H49NO12 

105 

Base  and  salts  crystal- 

Intensely 

napelline ; 

lise   with    difficulty. 

poisonous. 

feraconitine. 

Saponifiable. 

From        A. 

Ferox. 

Pseudaconine, . 

Saponification 

C27H41NO9 

100 

Amorphous ;        forms 

Bitter;  slightly 

of  pseudaconi- 

amorphous        salts. 

poisonous. 

tine. 

Does      not      reduce 
Fehling's  solution. 

Japaconitine,  . 

Crystalline 

C66H88N2O21 

184-186 

Crystallisable ;     forms 

Very     poison- 

alkaloid of 

crystallisable     salts. 

ous;   closely 

Japanese 

Saponifiable. 

resembles 

aconite  root. 

aconitine. 

Japaconine,     . 

Saponification 

C26H41NO9 

... 

Amorphous ;        forms 

Closely  resem- 

of   japaconi- 

amorphous  salts.  Re- 

bles aconine. 

tine. 

duces  Fehling's  solu- 
tion. 
Base  crystallises  with 

Picraconitine,  . 

Doubtful ;  per- 

C3iH46NOio 

above 

Bitter ;       not 

haps  the  in- 

100 

difficulty:   but  salts 

poisonous. 

active    alka- 

easily.   Saponifiable. 

loid     of    A. 

paniculatum. 

Picraconlne,    . 

Saponification 
of  picraconi- 
tine. 

C24H4iN09 

... 

Amorphous. 

Bitter;       not 
poisonous. 

Lyaconitine,     , 

From   root   of 
A.         lycoe- 
tonum. 

C27H34N2O6 

112-114 

Amorphous ;      dextro- 
rotatory.     Saponifi- 
able. 

Poisonous. 

Myoctonine,     . 

With  lyaconi- 

C40H56N2O12 

144 

Amorphous ;      dextro- 

Bitter ;     para- 

tine,   in    A. 

rotatory.       Saponifi- 

lytic poison. 

lycoetonum. 

able. 

Lyaconine, 

Lycoctonine. 
Saponifica- 

C27H47N207 

46 

Crystallisable ;  dextro- 
rotatory. 

Poisonous. 

Acolyctihe.      . 

tion  of  lya- 

conitine. 

With  lyaconine. 



... 

White  powder. 

Paralytic 

Atisine,     . 

From   root   of 

C46H74N204 

85 

Forms          crystalline 

poison. 
Bitter ;        not 

A.       hetero- 

haloid  salts. 

poisonous. 

phyllum. 

It  is  not  probable  that  either  the  foregoing  list  or  that  on  last 
page  includes  all  the  distinct  alkaloidal  principles  of  the  aconites. 
The  so-called  "  amorphous  alkaloids  "  have  been  very  imperfectly 


SAPONIFICATION   OF  ACONITE   BASES.  203 

examined,  owing  to  the  difficulty  of  obtaining  them  in  a  condition 
of  purity.  Of  those  which  have  been  partially  examined,  con- 
siderable uncertainty  exists  as  to  how  far  they  are  natural  con- 
stituents of  the  original  plant,  and  how  far  formed  by  polymerisa- 
tion or  other  changes  during  the  process  of  extraction.  T.  and  H. 
Smith  obtained  from  the  fresh  juice  of  the  roots  of  A.  NapelltL» 
an  alkaloid  which  appeared  to  be  narcotine,  and  which  they 
termed  aconelline.  The  occurrence  of  this  base  has  not 
been  confirmed,  but  it  is  noteworthy  that  there  is  a  relation 
in  the  constitution  of  narcotine  and  pseudaconitine ;  for,  while 
the  former  yields  m e  c o n i n,  G^^kP^,  or  opianic  acid, 
CioHj^Og,  on  saponification,  the  latter  gives  dimethyl-proto- 
catechuic  acid.  The  following  f ormulsB  show  the  constitu- 
tion of  the  two  last-named  bodies. 

C  O.CH3  (  O.CH3 

p    TT       )    O.CH3  p    TT       J     O.CH3 

^6^2^  CO.OH  ^6^2  ^  CO.OH 


1 


CO.H  (,  H 

Opianic  acid.  Dimethyl-protocatechuic  acid. 

The  researches  of  C.  R.  Alder  Wright  have  demonstrated 
that  the  crystallisable  alkaloids  of  Aconitum  Napellus^  A.  ferox, 
and  A.  Fischeri  (Japanese  aconite)  are  alkyl  salts  or  esters,  either 
of  benzoic  acid  itself  or  of  a  derivative  of  this  acid.  Thus,  when 
heated  with  alkalies  or  mineral  acids,  or  to  some  extent  when 
heated  with  water  alone,  each  of  the  crystalline  bases  undergoes 
saponification,  with  formation  of  benzoic  acid,  or  a  derivative 
thereof,  together  with  a  new  amorphous  base  of  far  less  physio- 
logical activity  than  the  crystalline  alkaloid  from  which  it  is 
derived.^ 

The  following  table  shows  the  composition  of  the  natural 
crystallisable  alkaloids  of  the  group,  and  the  products  of  their 
saponification.  The  formulae  of  aconitine  and  aconine  are 
those  attributed  to  these  bases  by  Dunstan  and  I n c e 
{Jour.  Chem.  Soc,  lix.  271),  and  show  Hg  more  in  the  mole- 
cule than  the  formulas  of  Alder  Wright  for  the  same 
alkaloids. 

1  The  statement  made  in  the  text  requires  qualification.  Picraconitine 
is  a  saponifiable  alkaloid,  but  is  not  poisonous.  It  forms  readily  crystal- 
lisable salts,  but  the  free  base  has  not  been  obtained  crystallised.  Atisine, 
again,  is  itself  amorphous,  but  forms  crystallisable  haloid  salts,  and  i& 
not  known  to  be  saponifiable.  Lyaconitine  and  myoctonine  have  not 
been  obtained  crystallised,  but  are  saponifiable  and  yield  crystallisable 
salts. 


204 


SAPONIFICATION   OF  ACONITE  BASES. 


CRTSTATiTJNB  BASE. 

Products  op  Hydrolysis. 

Amorphous  Base. 

Acid. 

Acoaitine, 

C33H45NO12 

Picrdconitine, 
C31H40NO10 

Japaconitine, 

C66H88N2O21 

Pseudaconitine, 
C36H49NO12 

Aconine, 

C26H41NO11 

Picraconine, 

C24H:4iN09 

Japaconine, 

2C26H41NO10 

Pseudaconine, 
C27H41NO9 

Benzoic  acid, 
C7H6O2 

Benzoic  acid, 
C7H6O2 

Benzoic  acid, 
2C7H6O2 

Veratric  acid  (dimethyl- 
protocatechuic  acid), 
C9H10O4 

Lyaconitine,  the  amorphous  alkaloid  of  A.  lycoctonum^  also 
yields  an  acid  and  one  or  more  bases  on  saponification  (of 
which  one,  lycoctonine,  readily  crystallises),  but  it  is 
doubtful  if  the  reaction  can  be  expressed  by  any  simple  formula 
(see  page  223).  The  amorphous  alkaloid  myoctonine,  from  the 
same  source,  yields  benzoic  acid  on  saponification,  together  with 
the  crystalline  base  lycoctonine,  and  other  products. 

The  saponification  of  the  crystalline  aconite  bases  occurs  with 
a  near  approach  to  quantitative  accuracy,  at  least  so  far  as  the 
production  of  the  acid  products  is  concerned ;  the  basic  product 
usually  undergoing  some  further  change  with  formation  of  a 
resinous  substance.  The  reaction  is  best  effected  by  boiling  the 
alkaloid  with  alcoholic  caustic  soda  for  some  time,  under  a 
reflux  condenser.  If  the  product  be  then  acidulated  with  hydro- 
chloric acid,  and  agitated  with  ether,  the  acid  products  of  the 
saponification  are  dissolved.  On  separating  the  ethereal  solution, 
and  shaking  it  with  soda,  the  benzoic  and  veratric  acids  are 
dissolved,  while  resinous  matter  remains  in  the  ether.  On  again 
acidulating  the  separated  alkaline  liquid  the  acids  are  liberated, 
and  may  be  dissolved  out  by  agitation  with  ether.  After  allowing 
the  washed  ethereal  solution  to  evaporate  spontaneously,  and  drying 
the  residue  over  sulphuric  acid,  the  acids  may  be  weighed;  or, 
where yOnly  one  is  present,  the  amount  may  be  ascertained  by 
titrating  the  ethereal  solution  with  standard  alkali  and  phenol- 
phthalein.  A  method  adapted  for  the  assay  of  very  small  quantities 
of  the  aconite  bases,  and  based  on  this  principle,  is  described  on 
page  234.  After  weighing,  the  melting-point  of  the  acid  may  be 
ascertained.  Benzoic  acid  melts  at  121°  C,  and  may  be  separated 
from  veratric  acid  (page  218)  by  prolonged  distillation  with  water, 
when  only  the  former  body  passes  over.  The  distillate  may  be 
rendered  alkaline,  concentrated  to  a  small  bulk,  acidulated,  and  the 


ANHYDRO   ACONITE  BASES. 


205 


benzoic  acid  extracted  with  ether,  and  recovered  by  evaporation  of 
the  solution.  The  veratric  acid  may  be  similarly  recovered  from 
the  liquid  left  in  the  retort. 

The  following  table  shows  the  proportions  of  carbon  and 
hydrogen  contained  in  the  crystallisable  aconite  bases,  together 
with  the  percentage  of  gold  contained  in  their  aurochlorides 
(dried  at  100°),  and  the  proportion  of  acid  yielded  on  saponi- 
fication : — 


Alkaloid. 

Formula. 

Carbon. 

Hydrogen. 

Gold  in 

Auro- 

chloride. 

Add  by 
Saponifi- 
cation. 

1 
NaHO 
required 

for 
Saponifi- 
cation. 

Aconitine,     . 
Pseudaconitine,    . 
Picraconitine, 
Japaconitine, 

C33H46NO12 
C36H49NO12 
C31H46NO10 

C66H88N2021 

61-20 
62-88 
62-95 
63-67 

6-95 
7-13 
7-61 

7-07 

19-96 
19-10 
21-07 
20-89 

18-92 
26-49 
20-60 
19-60 

6-20 
5-82 
6-77 
6-43 

When  the  hydrolysis  of  the  natural  aconite  bases  is  effected 
by  heating  with  concentrated  mineral  acids,  or  even  by  water  alone 
under  high  pressure,  the  saponification  is  preceded  or  accompanied 
by  the  removal  of  the  elements  of  water  and  a  formation  of  the 
so-called  "  apo-bases,"  preferably  called  anhydro-bases.  The  follow- 
ing table  shows  the  relation  of  the  apo-  or  anhydro-bases  to  their 
parent  alkaloids,  and  exhibits  the  constitutional  formulse  of  the 
former : — 

Alkaloid.  Anhydro-base. 


Aconitine. 

{OH 
OH 
O.CO.CeHg 

Aconine. 

OH 

^25237^^7^  OH 
OH 


Anhydro-aconitine. 

0 


C26H37NO.  ■(  OH 


O.CO.C^H, 


Anhydro-aconine. 

CgsHa^NOy^  OH 

(oh 


C27H37NO6 


Pseudaconitine. 

OH 
OH 
OH 
O.CO.C6H3(OCH3)2 


C27H37NO5 


Anhydro-pseudaconitine. 

0 

OH 

O.CO.C6H3(OCH3)^ 


206  ACETYL   AND   BENZOYL    DERIVATIVES. 

Pseudaconine.  Anhydro-pseudaconine. 

(oh  (0 

€27^37^0,  ^  ^g  C^^s,^'0,  ^  OH 

(oh  ^^^ 

The  anhydro-bases  are  best  prepared  by  heating  the  parent 
alkaloids  to  100°  for  six  to  ten  hours  with  a  saturated  aqueous 
solution  of  tartaric  acid.  On  rendering  the  liquid  alkaline  with 
sodium  bicarbonate,  and  shaking  with  ether,  the  anhydro-base  is 
dissolved,  and  may  be  obtained  in  crystals  on  evaporation  of  the 
ethereal  solution. 

In  their  physiological  effects,  the  anhydro-bases  resemble  the 
alkaloids  from  which  they  are  derived.  Thus  "  apo-aconitine,"  or 
anhydro-aconitine,  is  extremely  poisonous,  while  anhydro-aconine 
is  nearly  inactive. 

Japaconitine,  the  natural  alkaloid  of  Japanese  aconite  root, 
undergoes  no  further  change  when  heated  with  tartaric  acid, 
for  it  has  the  constitution  of  a  sesquianhydro-derivative  : — 

C,eH3,N0,i  O.CO.C,H, 

r 

C,,H3,N0j0.C0.CeH, 

The  hydrogen  of  the  OH-groups  of  the  anhydro-bases  is  capable 
of  replacement  by  organic  acid-radicals.  Thus  when  pseudaconitine 
is  heated  to  100°  for  some  hours  with  a  large  excess  of  glacial  acetic 
acid,  it  loses  the  elements  of  water,  but  the  anhydro-base  formed 
is  then  further  acted  on  with  formation  of  acetyl-anhydro- 
pseudaconitine,  which  is  a  base  crystallising  (like  the 
parent  alkaloid  and  its  anhydro-base)  with  IHgO,  forming  a  crys- 
talline nitrate  and  gold  salt,  and  yielding  acetic  and  dimethyl- 
protocatechuic  acids  on  saponification  with  alkalies.  The  same 
product  is  obtained  if  acetic  anhydride  be  used  in  place  of  acetic 
acid ;  while,  if  benzoic  anhydride  be  substituted  the  corresponding 
b  e  n.z  o  y  1-d  erivative  is  produced.  When  aconitine  is  heated 
withlbenzoic  anhydride  it  yields,  in  a  similar  manner,  benzoyl- 
anhydroaconitine,  a  product  which  is  apparently  identical 
with  that  obtained  by  the  action  of  benzoic  anhydride  on  aconine. 

/OH 

I  r)XT 

Aconitine,         ....     CagHgyNOyK  ^tt 

(oBz 


ACONITINE.  207 

Anhydroaconitine,      ,         .         ,     CofiH^y^OyK  OH 

(  OEz 

Benzoyl-anhydroaconitine  or  Di-  \  p   tt   -s^r)  J  ^tj 
benzoyl-anhydroaconine,       .  j  ^26^37^  ^7  i  ^^^ 

Japaconitine  is  converted  by  benzoic  anhydride  into  a  derivative 
containing  four  benzoyl-groups,  CgeHggNO^^O.Bz)^.  The  fact  may 
be  utilised  for  distinguishing  the  alkaloid  of  Japanese  aconite 
from  true  aconitine  as  described  on  page  221. 

Aconitine.     IN'apaconitine.     Benzoyl-aconine. 

C33H45NO12;  or  C2eH3,NO,(OH)3.0.CO.CeH5. 

Aconitine  is  the  crystalline  alkaloid  of  the  root  of  Aconitum 
Napellus,  Monk's-hood  or  Wolf's-bane  (French,  Coque- 
luchon ;  German,  Eisenhut,  Sturmhut).  It  exists  in  combination 
with  aconitic    acid,  CgHgOg  (Vol.  I.  p.  452). 

Aconitine  is  extremely  difficult  to  obtain  in  a  state  of  purity, 
owing  to  the  facility  with  which  it  is  converted  into  an  a  n  h  y  d  r  0- 
b  a  s  e,  and  suffers  hydrolysis  with  formation  of  the  amorphous 
base  aconine,  if  a  mineral  acid  be  employed  in  its  extraction.^ 

Alder  Wright  found  that  the  whole  of  the  alkaloid  could  be 
extracted  by  alcohol  from  Japanese  aconite  root  without  the  addition 
of  any  acid ;  and  the  same  appears  to  be  true  of  the  root  of  other 
species  of  aconite.     Thus  C.  F.  Bender  (Pharm.  CentralU.^  xxvi. 

^  One  of  the  best  methods  of  preparing  aconitine  from  aconite  root  is  that  of 
Duquesnel  {Jour.  Pharm.  et  Chimie,  [4],  xiv.  94),  who  exhausts  the 
material  in  the  cold  with  rectified  spirit  to  which  has  been  added  a  small 
amount  of  tartaric  acid.  The  alcoholic  solution  is  distilled  out  of  contact  with 
the  air  at  a  temperature  not  exceeding  60°  C,  and  the  residue  diluted  with 
its  own  measure  of  water,  and  filtered  from  the  precipitated  resinous  and  fatty 
matters.  The  acid  liquid  is  next  agitated  with  ether  or  petroleum  spirit  to 
remove  colouring-matters,  and  then  rendered  alkaline  with  sodium  bicarbonate, 
which  precipitates  the  aconitine  and  a  portion  of  the  amorphous  bases,  a  large 
portion  of  the  latter  remaining  in  solution.  The  precipitated  alkaloid  is 
extracted  by  agitation  with  ether,  which,  on  evaporation  or  precipitation  by 
petroleum  spirit,  deposits  the  base  in  colourless  rhombic  tables,  which  some- 
times appear  hexagonal  in  consequence  of  the  modification  of  the  acute  angles. 
The  aconitine  thus  obtained  is  contaminated  by  an  admixture  of  amorphous 
alkaloid,  which  clings  to  it  with  great  obstinacy,  and  cannot  be  removed 
simply  by  crystallisation  ;  but  by  converting  the  base  into  the  hydrochloride, 
or  preferably  the  hydrobromide,  recrystallising  the  salt,  and  liberating  the 
alkaloid  by  sodium  carbonate,  a  product  is  obtained  which,  when  recrystal- 
lised  from  ether,  is  very  pure. 


208  PREPARATION    OF   ACONITINE. 

433)  has  applied  extraction  by  unacidulated  alcohol  to  the  pre- 
paration of  pure  aconitine,  and  the  B.P.  process  is  based  on  the 
same  principle.  R.  Wright  {Pharm.  Jour.^  [3],  xx.  375)  found 
that  chloroform  alone  did  not  extract  nearly  all  the  alkaloid  from 
aconite  root.  By  first  moistening  the  root  with  ammonia,  drying 
it  carefully,  and  then  percolating  with  chloroform,  T.  B.  Groves 
obtained  a  much  better  yield  than  with  chloroform  alone.  John 
Williams  employed  amylic  alcohol  for  extracting  aconitine.^ 

For  the  final  purification  of  aconitine,  D  u  n  s  t  a  n  and  I  n  c  e 
{Jour.  Ghem.  Soc,  lix.  271)  employed  solution  of  the  base  in  cold 
dilute  hydrochloric  acid,  and  addition  of  auric  chloride  in  quantity 
sufficient  to  precipitate  one-fifth  of  the  alkaloid  present.  The 
amorphous  alkaloid  was  wholly  precipitated,  and  from  the  filtrate 
the  pure  aconitine  was  precipitated  by  sodium  carbonate,  and 
when  crystallised  from  ether-alcohol  was  obtained  in  large,  flat, 
rhombic  prisms  with  truncated  ends,  which  appeared  as  hexagonal 
plates  under  the  microscope.^  D  u  n  s  t  a  n  and  I  n  c  e  {Jour.  Ghem. 
Soc,  lix.  271)  attribute  to  the  pure  aconitine  obtained  by  the  above 
method  the  composition  CggH^gNOig,  which  differs  by  Hg  from 
the  formula  of  Alder  Wright;  but  the  method  of  combustion 
on  which  both  formulae  are  based  is  scarcely  delicate  enough  to 
decide   between   the    two,  and  as   hydrogen-determinations   have 

^  The  following  is  an  outline  of  the  method  of  preparing  crystallised  aconi- 
tine ultimately  practised  by  J.  Williams  (and  posthumously  published 
by  Richards  and  Rogers,  Chemist  and  Druggist,  Feb.  7,  1891),  being  an 
improvement  on  the  process  previously  described  by  him  (Pharm.  Jour. ,  [3], 
xviii.  238) : — The  aconite  root  is  coarsely  ground  and  macerated  in  the  cold 
for  three  or  four  days  with  amylic  alcohol,  which  solvent  removes  both  the 
free  base  and  its  salts.  The  solution  is  shaken  with  successive  small  quantities 
of  water  slightly  acidulated  with  sulphuric  acid  (^  fluid  ounce  to  the  gallon). 
The  last  washings  should  retain  a  distinct  acid  reaction,  and  the  liquor  should 
be  examined  to  insure  complete  extraction  of  the  alkaloid.  The  acid  liquid 
is  then  shaken  several  times  with  washed  ether,  to  remove  amylic  alcohol  and 
colouring-matter,  and  then  gently  warmed  to  dissipate  the  remaining  ether. 
"When  quite  cold  the  solution  is  treated  with  sodium  carbonate,  and  the  pre- 
cipitated alkaloid  filtered  off,  pressed,  and  dried  by  exposure  to  air.  When 
dry,  it  is  boiled  for  some  time  with  ether  (previously  washed  with  water  and 
dried  by  potassium  carbonate),  and  the  solution  filtered  hot  into  a  basin, 
when  nearly^he  whole  of  the  alkaloid  will  crystallise  out.  The  ring  of  un- 
crystallisable  gummy  matter  which  forms  at  the  edge  of  the  dish  can  be 
dissolved  by  a  little  cold  ether,  in  which  the  crystals  are  only  sparingly 
soluble. 

2  The  microscopic  appearance  of  aconitine  is  regarded  by  Richards  and 
Rogers  as  the  best  and  most  characteristic  test  of  the  alkaloid  {Chemist  and 
Druggist,  May  18  1889).  Crystallisation  is  best  effected  from  somewhat 
dilute  alcohol. 


CHARACTERS   OF   ACONITINE.  209 

notoriously  a  tendency  to  be  in  excess  of  the  truth,  the  H^g  formula 
is  quite  as  probable  as  the  other. 

Aconitine  is  only  very  sparingly  soluble  in  cold  water,  requiring 
726  parts  at  the  ordinary  temperature,  according  to  Jiirgens, 
and  nearly  ten  times  this  proportion,  according  to  J  C.  U  m  n  e  y 
In  hot  water  it  dissolves  more  freely,  and  is  soluble  in  24  parts  of 
rectified  spirit,  readily  in  chloroform  and  benzene,  and  moderately 
in  ether ;  but  is  almost  insoluble  in  carbon  disulphide  and  petro- 
leum spirit,  and  is  precipitated  by  the  latter  from  its  solution  in 
benzene  or  ether.  It  is  not  extracted  from  its  acidulated  solutions 
by  any  ot  these  solvents. 

Aconitine  has  a  slightly  bitter  taste,  the  intensity  of  which  is 
said  to  be  inversely  as  its  purity.  It  is  extremely  poisonous. 
Solutions,  sufficiently  dilute  to  be  safely  employed,  cause  a 
characteristic  tingling  and  numbness  of  the  lips,  tongue,  and 
pharynx.  ^ 

Pure  aconitine  is  stated  by  Dunstan  and  I n c e  to  melt  at 
ISe^'S  C.  (corrected),  but  Duquesnel  gives  140°,  Alder 
Wright  183°-184°,  and  Jiirgens  179°.  The  material  of  the 
earlier  observers  was  probably  sensibly  impure,  but  the  want  of  con- 
cordance may  be  due  in  part  to  the  mode  of  heating  the  alkaloid. 
Thus  when  slowly  heated  aconitine  melts  at  a  lower  temperature 
than  when  heated  quickly.  Dunstan  and  I  n  c  e  recommend 
the  use  of  a  bath  of  paraffin,  long  enough  to  entirely  immerse 
the  stem  of  the  thermometer.  The  bath  is  heated  to  about  150°, 
before  the  thermometer  with  the  thin  glass  tube  containing  the 
alkaloid  is  immersed,  and  is  kept  well  stirred  throughout  the 
operation.2 

Aconitine  in  the  free  state  is  dextro-rotatory,  a  3  per  cent, 
solution  in  alcohol  having  a  specific  rotatory  power  of  -|-ll°'l  for 
the  sodium  ray.  On  the  other  hand,  the  salts  are  Isevo-rotatory,  the 
hydrochloride  in  aqueous  solution  showing  S^  =  —  35°'9.     Similarly 

^  Aconitine  is  probably  the  most  violent  poison  known,  t^  grain  is  the 
ordinary  medicinal  dose,  and  ^V  grain  a  fatal  dose  for  an  adult.  In  working 
with  aconitine,  great  care  must  be  taken  to  avoid  the  action  of  the  base  and  its 
salts,  especially  in  the  solid  state.  A  minute  fragment  of  the  dust,  too  small 
to  be  seen,  if  accidentally  blown  into  the  eye,  sets  up  the  most  painful  irrita- 
tion and  lachrymation,  lasting  some  hours  ;  while,  if  inhaled,  a  like  amount 
will  produce  great  bronchial  irritation  or  profuse  sneezing,  and  considerable 
catarrh  or  sore  throat  (C.  R.  A 1  d  e  r  W  r  i  g  h  t). 

^  Alder  Wright  states  that  aconitine  melts  in  a  capillary  tube  at  183°- 
184°  (corrected).  The  final  complete  melting  is  preceded  by  a  slight  fritting 
beginning  a  few  degrees  below  the  melting-point,  which  is  lowered  by  the 
presence  of  amorphous  bases.  With  pure  aconitine  very  slight  darkening 
occurs,  but  it  is  more  marked  with  impure  material. 

VOL.  III.  PART  H.  0 


210  SALTS  OF  ACONITINE. 

the  crystalline  hydrobromide,  CggH^gNO^gHBr  -|-  2^  aq.,  gives 
So=  —  30°'5  in  2  per  cent,  aqueous  solution. 

Salts  of  Aconitine. 

Aconitine  has  well-marked  basic  properties,  ana  forms  a  series 
of  crystallisable  salts.  Caustic  alkalies,  fixed  alkaline  carbonates 
and  ammonia  (but  not  am.moniuni  carbonate  or  fixed  alkaline 
bicarbonates),  throw  down  the  free  base  from  the  solutions  ol  its 
salts  as  a  white  flocculent  precipitate,  practically  insoluble  in  excess 
of  the  reagent. 

The  salts  of  aconitine  with  the  mineral  acids  are  neutral  to 
methyl-orange  and  rosolic  acid,  but  may  be  titrated  with  stan- 
dard caustic  alkali  and  phenolphthalein,  just  as  if  the  acid  existed 
in  a  free  state. 

Aconitine  Aconitate  exists  ready-formed  in  aconite  root.  It  is 
gummy  in  appearance,  and  crystallises  with  difficulty.  It  dissolves 
in  water,  alcohol,  amylic  alcohol,  and  chloroform;  and  is  partially 
precipitated  from  its  solution  in  the  last  menstruum  by  the  addition 
of  ether. 

Aconitine  Nitrate  is  readily  obtained  by  dissolving  aconitine  in 
dilute  nitric  acid,  and  then  adding  gradually  an  excess  of  moder- 
ately strong  nitric  acid,  when  the  salt  separates  in  a  bulky  form, 
rendering  the  mixture  semi-solid.^  When  pressed  to  separate  the 
mother-liquor,  and  recrystallised  from  water,  it  forms  rosettes  or 
fine  rhombic  and  short  prismatic  crystals,  which  are  colourless  and 
transparent,  but  slightly  efflorescent. 

The  aconitine  nitrate  thus  prepared  has  a  very  anomalous  com- 
position, containing  as  it  does  £2(11^03)3.^  The  neutral  nitrate, 
BHNO3,  is  obtainable  as  an  amorphous  residue  by  evaporating  a 
solution  in  an  equivalent  quantity  of  dilute  nitric  acid. 

Aconitine  nitrate  is  only  sparingly  soluble  in  cold  water;  but 

*  According  to  J.  "Williams  {Year-BooTc  Pharm.^  1886,  433),  when 
aconitine  is  recovered  from  the  nitrate  prepared  in  this  way  it  crystallises  in 
a  different  manner  from  the  original  alkaloid.  This  experience  is  confirmed 
by  Richards  and  Rogers  {Chemist  arirfZ'rwf/pfts^,  May  18, 1889,  andFeb. 
14,  1891),  who  attribute  a  greatly  increased  physiological  activity  and  slightly 
reduced  melting-point  to  tlie  alkaloid  thus  recovered.  This  interesting  result 
may  possibly  be  due  to  the  partial  or  complete  conversion  of  the  original 
alkaloid  into  anhydroaconitine  (page  213)  by  the  action  of  the  strong 
acid  employed.  If  this  suggestion  be  well  founded,  the  anliydroaconitine 
could  be  separated  as  indicated  on  page  214. 

2  A.  Jiirgens  found  crystallised  aconitine  nitrate,  dried  at  100°,  by 
titration  with  caustic  alkali  and  phenolphthalein,  to  contain  a  proportion  of 
nitric  acid  corresponding  to  the  sesqui-nitrate  (1271  per  cent.),  while  one- 
third  of  this  was  indicated  by  rosolic  acid  (Inaugural  Dissertation,  Dorpat 
1886). 


ACONITINE  AUROCHLOKIDE.  211 

it  dissolves  easily  in  water  saturated  with  carbonic  acid,  and 
gradually  crystallises  as  the  gas  escapes  from  the  liquid. 

Aconitine  Sulphate  is  obtained  by  evaporation  of  its  solution  at 
a  gentle  heat  as  a  vitreous  non-deliquescent  mass,  which  appears 
under  the  microscope  as  a  confused  mass  of  crystals. 

Aconitine  Hydrohr amide,  C^^^^O^^^^t,  crystallises  readily  in 
monoclinic  tables  containing,  according  to  Jiirgens,  2J  aqua. 

Aconitine  Hydrochloride^  CggH^gNOig.HCl,  is  obtained  by  slow 
evaporation  of  its  solution  in  large  rhombic  crystals  which,  accord- 
ing to  J  ii  r  g  e  n  s,  contain  3  aqua. 

Aconitine  Aurochloride,  CggH^gNOjgjHAuCl^,  is  thrown  down  as 
a  yellow  amorphous  precipitate  on  adding  auric  chloride  to  a 
solution  of  aconitine  hydrochloride,  or  to  the  salt  of  the  alkaloid 
to  which  sodium  chloride  or  hydrochloric  acid  has  been  added. 
The  precipitate  is  formed  even  in  very  dilute  solutions,  and  is  only 
very  sparingly  soluble  in  dilute  hydrochloric  acid.  It  dissolves 
readily  in  absolute  alcohol,  methyl  alcohol,  chloroform,  and 
acetone,  but  less  readily  in  ether  and  dilute  alcohol.  The  com- 
pound can  be  crystallised  from  alcohol,  the  deposition  being 
facilitated  by  the  cautious  addition  of  water.  When  pure,  aconitine 
aurochloride  melts  at  135°'5  (corrected),  but  a  very  small  propor- 
tion of  impurity  tends  to  reduce  the  melting-point  to  130°,  or  less. 
From  a  solution  of  impure  aconitine  hydrochloride,  the  impurities 
are  thrown  down  first,  on  gradual  addition  of  auric  chloride. 
Duns  tan  and  Ince  recommend  the  preparation  of  the  auro- 
chloride and  the  determination  of  its  melting-point  as  a  reliable 
means  of  identifying  aconitine,  especially  as  the  pure  alkaloid  can 
be  readily  recovered  in  a  crystalline  state  from  the  compound. 
The  only  successful  method  of  effecting  this,  out  of  a  large  number 
tried,  was  to  grind  the  aurochloride  to  a  fine  powder  with  water, 
and  add  sulphuretted  hydrogen  water,  drop  by  drop,  till  the  gold  is 
wholly  precipitated  as  sulphide.  An  excess  of  the  reagent  should 
be  avoided.  The  liquid  is  then  filtered,  a  current  of  air  passed  to 
remove  any  slight  excess  of  sulphuretted  hydrogen,  sodium  bicar- 
bonate added  in  slight  excess,  and  the  liberated  alkaloid  extracted 
by  agitation  with  ether. 

On  mixing  alcoholic  solutions  of  free  aconitine  and  auric  chloride, 
and  gradually  adding  water,  aconitine  gold  chloride, 
BAuClg,  is  precipitated.  When  recrystallised  from  alcohol  the 
compound  melts  at  129°. 

Chemical  Reactions  of  Aconitine. 

A  solution  of  iodine  in  iodide  of  potassium  produces  a  reddish 
brown  or  yellowish  amorphous  precipitate,  even  in  very  dilute 
(1  :  20,000)   acidulated  solutions    of   aconitine.     Mayer's  leagent 


212  REACTIONS   OF   ACONITINE. 

precipitates  aconitine  solutions,  if  not  more  dilute  than  1  in  10,000, 
and  may  be  used  foi  the  determination  of  the  alkaloid.  Phos- 
phomolybdic  acid  also  precipitates  moderately  dilute  solutions 
(1  :  5000),  and  if  the  aconitine  be  pure  the  precipitate  dissolves 
in  ammonia  without  blue  coloration.  Phosphotungstic  acid  behaves 
similarly.  Picric  acid  precipitates  solutions  which  are  not  too 
dilute ;  but  mercuric  chloride  gives  no  reaction  with  aconitine 
solutions  much  below  1  per  cent,  in  strength ;  while  platinic  chlo- 
ride, and  potassium  chromate,  iodide,  ferrocyanide  and  ferricyanide 
fail  to  precipitate  aconitine  solutions  unless  very  concentrated. 

According  to  A.  Jiirgens  (Arch.  Phar7n.,[3],  xxiv.  127,  172) 
aconitine  can  be  identified  under  the  microscope  by  dissolving  a 
minute  quantity  in  water  acidulated  with  acetic  acid,  and  adding  a 
particle  of  potassium  iodide.  On  allowing  the  solution  to  evaporate, 
characteristic  crystals  of  aconitine  hydriodide  appear,  and  remain 
after  adding  water  to  dissolve  the  crystals  of  potassium  iodide 
simultaneously  formed. 

An  alcoholic  solution  of  aconitine  reduces  silver  nitrate,  but  no 
reduction  is  produced  by  the  salts  of  aconitine. 

A  mixture  of  solutions  of  potassium  ferricyanide  and  ferric 
chloride  is  turned  blue  by  aconitine. 

Aconitine,  when  pure,  gives  no  marked  colour-reactions,  but  as 
extracted  from  the  tincture  and  other  pharmaceutical  preparations, 
by  adding  an  alkali  and  agitating  with  ether,  it  yields  certain 
colour-reactions  which  are  serviceable  as  supplementary  tests  for 
the  aconitine-alkaloids  generally  (see  page  242).  The  most 
characteristic  property  of  pure  aconitine  is  its  physiological  action, 
which  may  be  supplemented  by  the  reactions  with  auric  chloride, 
potassium  iodide,  and  the  formation  of  benzoic  acid  and  aconine 
on  saponification. 

As  tests  for  the  purity  of  aconitine.  Alder  Wright  recom- 
mends the  observation  of  the  melting-point,  supplemented  by  the 
following: — The  alkaloid  is  dissolved  in  a  few  drops  of  dilute 
acid,  pure  ether  adjied,  and  then  excess  of  sodium  carbonate 
solution;  the  whole  being  well  agitated  in  a  stoppered  bottle. 
The  ethereal  solution  is  then  separated  and  allowed  to  evaporate 
spontaneously.  When  only  a  small  volume  is  left,  this  is  poured 
away  from  the  deposited  crystals,  and  allowed  to  evaporate  com- 
pletely. If  the  aconitine  were  tolerably  pure,  the  last  drops  of  the 
ethereal  solution  will  leave  a  crystalline  residue  ;  but  if  more 
than  minute  quantities  of  amorphous  bases  be  present,  these  will 
accumulate  in  the  ethereal  mother-liquor,  the  last  portions  will 
leave  a  varnish  or  gummy  residue  on  evaporation. 

When  strictly  imre,  aconitine  dissolves  without  colour  in  sulphuric 


DECOMPOSITION   OF  ACONITINE.  213 

acid ;  and  on  adding  a  few  drops  of  concentrated  syrup  no  red 
coloration  should  be  produced,  even  after  standing  some  time. 

When  heated  for  some  hours  to  100°  C.  with  alcohol  and  caustic 
soda,  aconitine  should  yield  close  on  20  per  cent,  of  benzoic  acid, 
determined  as  on  page  234.  The  resulting  acid  should  melt  at 
120°,  and  should  not  yield  any  protocatechuic  acid  on  fusion  at 
250°  with  caustic  potash.  This  and  the  other  reactions  described 
on  page  219  distinguish  aconitine  from  pseudaconitine.  From 
japaconitine,  aconitine  can  be  distinguished  by  its  crystalline  form, 
by  careful  determination  of  the  carbon  and  hydrogen  (compare 
page  204),  and  by  its  behaviour  with  acetic  and  benzoic  anhydrides. 
In  all  other  characters  the  two  alkaloids  closely  correspond. 

Aconitine  is  quite  unchanged  when  heated  to  100°  in  a  vacuum, 
and  but  very  slightly  altered  at  120°.  When  kept  for  an  hour  at 
its  melting-point  it  loses  about  10  per  cent,  of  its  weight,  and  the 
residue  consists  wholly  of  a  c  o  n  i  n  e,  CggH^-^NOj^. 

When  aconitine  is  heated  with  water  to  100°  for  many  hours 
in  a  sealed  tube,  it  is  hydrolysed  with  formation  of  aconine  and 
benzoic  acid :— C35H45NO12  +  HgO  =  Cg.H.iNOn  +  C^HgOg. 
The  reaction  is  apt  to  be  incomplete,  only  85  per  cent,  of  the 
base  being  hydrolysed  by  heating  with  water  in  sealed  tube  to 
1 40°  C.  for  twenty-four  hours.  By  mere  boiling  with  water  under 
a  reflux  condenser  for  a  few  hours,  the  alkaloid  is  practically  un- 
changed. If  ammonia  be  added  to  the  water,  a  small  but  appre- 
ciable decomposition  ensues.  Solutions  of  potassium  and  sodium 
carbonates  act  more  powerfully,  some  hydrolysis  occurring  even 
in  the  cold  after  prolonged  standing,  while  on  boiling  nearly  complete 
saponification  into  aconine  and  benzoate  ensues.  Caustic  alkalies 
rapidly  effect  the  same  decomposition,  especially  in  alcoholic  solution. 

When  aconitine  is  heated  with  a  dilute  mineral  acid  (especially 
hydrochloric  acid),  the  first  action  consists  in  the  removal  of  the 
elements  of  water  with  formation  of  apo-  or  anhydro- 
aconitine,  CggH^gNOji.  But  this  dehydration  is  rapidly 
succeeded  by  hydrolysis,  and  formation  of  aconine  and  ben- 
zoic acid,  just  as  when  alkalies  are  employed.  On  the  other 
hand,  the  weaker  organic  acids  do  not  eff'ect  this  hydrolysis,  or  do 
so  but  very  imperfectly.  Thus  aconitine  yields  no  appreciable 
quantity  of  benzoic  acid  when  heated  to  100°  C.  for  ten  hours, 
with  a  saturated  aqueous  solution  of  tartaric  acid ;  but  this  treat- 
ment effects  the  complete  conversion  of  the  alkaloid  into  apo-  or 
anhydro-aconitine. 

Anhydro-aconitine,  C33H43NO11,  is  best  obtained  by  heating 
aconitine  to  100°  with  a  saturated  solution  of  tartaric  acid.  On 
evaporating  the  ethereal  solution   of  the   base  it  is  obtained   in 


214  ACONINE. 

small  colourless  crystals,  which  cohere  and  stick  to  the  sides  of 
the  glass  vessel  in  a  characteristic  manner.  It  melts  at  186°*5, 
i.e.y  2°  lower  than  aconitine,  and  in  other  respects  (including  its 
poisonous  properties)  closely  resembles  the  parent  alkaloid.  An- 
hydro-aconitine  forms  crystalline  salts.  The  aurocliloride  forms 
an  amorphous  precipitate  which  dissolves  in  absolute  alcohol.  If 
the  solution  be  evaporated  in  vacuo  over  calcium  chloride,  the 
compound  BHAuCl^  is  deposited  in  crystals  melting  at  141°; 
but  if  the  alcoholic  solution  be  precipitated  by  gradual  addition 
of  water,  the  crystals  deposited  melt  at  129°,  and  contain 
CggH^gNOjpHAuCl^+HgO.  When  this  is  recrystallised  from 
dilute  alcohol  it  is  converted  into  aconitine  aurochloride, 
C33H45NOi2,HAuCl4,  melting  at  135°"5.  Anliydroaconitine  gold 
chloride,  BAuClg,  is  obtained  by  mixing  alcoholic  or  ethereal 
solutions  of  the  base  and  auric  chloride.  It  melts  at  147°'5,  and 
shows  no  tendency  to  pass  into  the  aconitine  salt  (D  u  n  s  t  a  n 
and  Ince,  Jour.  Ghem.  Soc,  lix.  284). 

Commercial  aconitine  is  liable  to  contain  the  anhydro-base, 
which  may  be  removed  by  converting  the  alkaloid  into  the 
hydrobromide,  and  crystallising  the  salt  from  water,  when  the  salt 
of  anhydro-aconitine  remains  in  the  mother-liquor. 

AcoNiNE,  CggH^^NOij,  probably  occurs  ready-formed  in  aconite 
root,  and  certainly  in  other  parts  of  the  plant.  It  may  be  obtained 
pure  by  boiling  aconitine  with  alcoholic  potash  or  soda  for  some 
hours,  distilling  off  the  alcohol,  acidulating  the  liquid  with  hydro- 
chloric acid,  and  removing  the  benzoic  acid  by  agitation  with 
ether.  On  rendering  the  solution  alkaline,  and  shaking  with 
chloroform  (aconine  being  reputedly  insoluble  in  ether),  the  base  is 
taken  up.^  On  adding  light  petroleum  gradually  to  the  chloroformic 
solution  the  aconine  is  precipitated.  The  first  portions  are  impure, 
but  the  last  fraction  is  nearly  free  from  colour,  though  still  resinous 
and  friable  when  dry. 

Aconine  melts  at  130°,  is  soluble  in  alcohol  and  chloroform,  and 
somewhat  soluble  in  water,  but  is  insoluble  in  anhydrous  ether, 
benzene,  and  petroleum  spirit.  Both  the  free  base  and  its  salts 
resist  all  attempts  to  crystallise  them.  The  solutions  yield 
amorphous  precipitates  with  the  usual  alkaloidal  reagents.  The 
aurocliloride,  BHAuCl^,  is  a  pale  yellow  amorphous  precipitate, 
which  is  deposited  in  oleo-resinous  films  on  evaporating  its  solu- 
tion in  alcohol  (D  u  n  s  t  a  n  and  Ince,  Jour.  Chem.  Soc,  lix.  286). 

*  The  author's  experience  is  that  if  the  alkahne  liquid  be  shaken  with  ether, 
the  greater  part  of  the  basic  saponification-product  (aconine)  is  extracted,  but 
that  a  small  additional  amount  of  base  can  be  recovered  by  subsequent  agita- 
tion  with  chloroform. 


AMOllPHODS  BASES.  215 

For  the  isolation  of  aconine  from  the  mixed  alkaloids  of 
A.  Napellus,  the  bases  are  dissolved  in  dilute  acid,  excess  of 
potassium  bicarbonate  added,  and  the  precipitated  aconitine  filtered 
off  or  extracted  by  ether.  The  filtrate  is  slightly  acidulated  and 
precipitated  by  potassio- iodide  of  mercury,  the  precipitate  sepa- 
rated, suspended  in  alcohol,  and  decomposed  by  sulphuretted 
hydrogen.  On  evaporating  the  filtered  liquid,  the  aconine  is 
obtained  as  a  resin  which  can  be  purified  by  treatment  with  ether, 
to  remove  colouring-matter  and  other  alkaloids,  solution  in  benzene, 
and  precipitation  by  petroleum  spirit.  But  the  product  is  always 
amorphous,  and  yields  amorphous  salts. 

Aconine  is  very  bitter  (far  more  so  than  aconitine),  but  does  not 
produce  tingling  of  the  gums,  and  has  very  little  physiological 
activity  {-^^q  that  of  aconitine).  It  is  also  distinguished  from 
aconitine  by  its  uncrystallisable  character,  its  readier  solubility  in 
water  and  insolubility  in  ether,  and  by  not  yielding  benzoic  acid 
when  boiled  with  alcoholic  potash  or  soda.  It  reduces  gold  and 
silver  salts  at  the  ordinary  temperature  and  Fehling's  solution 
on  heating.  It  gives  a  blue  coloration  when  added  to  mixed 
solutions  of  ferric  chloride  and  potassium  ferricyanide. 

Anlujdro-aconine,  C^^^^^O-^q,  is  obtained  by  heating  aconine 
hydrochloride  to  1 40°  The  base  and  salts  are  amorphous.  It  is 
bitter  and  very  feebly  poisonous. 

Amorphous  Saponifiable  Bases  of  Aconitum  Napellus. 

In  addition  to  aconitine,  the  active  and  crystalline  alkaloid  of  A. 
Napellus,  and  picraconitine,  which  appears  to  be  occasionally  present, 
indications  of  the  presence  of  another  saponifiable  alkaloid  have 
been  met  with  by  several  observers.  Thus  Alder  Wright  and  Luff 
{Jour.  Cliem.  Soc,  xxxiii.  318)  found  that  the  mother-lic^uors, 
from  which  as  much  crystalline  aconitine  as  possible  had  been 
separated,  contained  an  amorphous  base  showing  0  =  66*39,  and 
H  =  7"94  per  cent.,  and  which  gave  about  14  jDer  cent,  of  benzoic 
acid  on  saponification.  Wright  (private  communication  to  the 
author)  states  that  it  is  impossible  to  form  any  idea  of  the  pro- 
portion of  the  amorphous  saponifiable  base  present,  and  does  not 
regard  his  product  as  a  single  alkaloid,  but  believes  it  still  retained 
aconitine,  which  was  prevented  from  crystallising  by  the  amorphous 
bases  present.  He  thinks  it  probable  that  the  benzoic  acid  pro- 
duced on  saponification  was  mainly  derived  from  amorphous 
saponifiable  bases,  which  may  possibly  have  been  in  part  pre- 
existent  in  the  plant,  but  probably  were  chiefly  alteration-products 
of  aconitine,  just  as  the  amorphous  base  quinicine  results  from  the 
alteration  of  quinine. 

A.  Jiirgens  (Inaugural  Dissertation,  Dorpat,  1885)  has 
also    isolated   an   amorphous    saponifiable  base    from  the  root  of 


216  AMORPHOUS  ACONITE  BASES. 

A.  NapelluSf  and  found  it  to  contain  C  =  67*74,  H  =  8'40  per  cent., 
and  to  yield  an  unstated  proportion  of  benzoic  acid  and  a 
base  allied  to  aconine  on  saponification.^  BHCl,  BHBr,  BHI, 
BgHgSO^,  BHNO3  and  BHA  were  amorphous,  but  the  very  small 
quantity  of  material  at  disposal  prevented  any  complete  examina- 
tion of  the  alkaloid  being  made.  It  is  probable  that  the  amorphous 
saponifiable  base  of  A.  Napellus  bears  the  same  relation  to  aconi- 
tine  that  quinicine  bears  to  quinine,  and  is  a  polymeiide  of  the 
crystallisable  alkaloid.  Hence  the  name  aconicine  would 
appear  convenient  and  appropriate. 

J.  C.  Umney  states  that  the  amorphous  saponifiable  base  of  A. 
Napellm  produced  no  ill  effects  on  him  when  taken  in  ]  grain 
doses. 

PseudaCOnitine.       Feraconitine.      Yeratroyl-pseudaconine. 
C36H49NO12;  or  C2jH3,NO,(OH)3.0.CO.C6H3(OCH3)2 

Pseudaconitine  is  the  characteristic  crystalline  alkaloid  of 
Aconitum  ferox,  a  native  of  the  Himalayas,  and  is  stated  to  be  also 
present  in  A,  anthora,  and  other  species ;  also,  according  to  Alder 
Wright,  in  small  quantity  in  A.  napellus.^ 

^  The  remarks  made  byMrJohn  C.  Umney  before  the  British  Pharma- 
ceutical Conference  of  1891  (Pharm.  Jour.,  [3],  xxii.  223,  447;  Chemist  and 
Druggist,  xxxix.  293  ;  British  and  Colonial  Druggist,  xx.  210)  contained 
various  erroneous  statements  respecting  the  amorphous,  saponifiable  alkaloid 
of  A.  napellus.  These  statements,  the  reports  of  which  Mr  Umney  has 
declined  to  correct,  conveyed  to  his  auditors  the  false  impression  that  the 
recognised  proportion  of  the  inactive,  saponifiable  base  in  question  would 
suffice  to  double  the  proportion  of  benzoic  acid  produced  on  saponification, 
and  hence  would  invalidate  any  process  of  assay  based  on  that  reaction  (see 
page  233);  whereas  the  fact  is  that  in  no  investigation,  the  results  of  which 
liave  been  hitherto  published,  has  the  alleged  inactive  base  been  obtained  free 
from  aconitine,  or  in  the  considerable  proportion  erroneously  asserted  by  Mr 
Umney,  whose  mistakes  appear  to  have  arisen  in  part  through  confusion  be- 
tween the  base  in  question  with  amorphous  unsaponifiable  aconite  bases. 

^  According  to  a  more  recent  research  by  Jiirgens  {Pharm.  Zeit. ,  Sept. 
1887),  picraconitine  has  a  constitution  intermediate  between  aconitine  and 
aconine.  He  states  that  picraconitine  results  from  the  splitting  off  of  a 
single  benzoyl-radical  from  aconitine,  while  the  elimination  of  two  benzo3'l- 
groups  results  in  the  formation  of  aconine;  but  that  in  the  decomposition 
of  aconitine,  not  only  benzoyl  but  methyl  groups  are  split  off.  No  detailed 
account  of  this  suggestive  investigation  appears  to  have  been  published. 

'  "The  report  that  Morson's  aconitine  is  pseudaconitine  from  Himalaya 
bikh  tubers  is  now  tolerably  well  disposed  of,  since  Morson  has  made  it  known 
that  his  aconitine  is  prepared  from  the  tubers  of  cultivated  Aconitum 
Napellus"  (Husemann,  Pharm.  Zeit.,  1884).  At  one  time,  Morson's  aconi- 
tine was  certainly  prepared  from  A,  ferox. 


PSEUD  AGON  ITINE.  217 

Pseudaconitine  is  readily  obtained  pure  by  dissolving  the 
mixture  of  alkaloids  isolated  from  the  root  of  A  ferox  in 
dilute  nitric  acid,  and  then  gradually  dropping  in  strong  nitric 
acid  with  constant  stirring,  until,  by  the  separation  of  the  nitrate 
of  pseudaconitine,  the  liquid  becomes  thick.  It  is  then  drained  by 
means  of  a  filter-pump,  and  washed  slightly  with  water  containing 
8  to  10  pel  cent,  of  nitric  acid.  If  a  perfectly  pure  salt  be  re- 
quired, the  product  is  purified  by  re-solution  in  the  least  possible 
quantity  of  hot  water,  cooling,  and  dropping  in  strong  nitric  acid 
till  the  salt  crystallises ;  when  it  is  drained,  pressed,  and  the  alka- 
loid liberated  by  treating  the  solution  with  sodium  carbonate 
Crystallised  pseudaconitine  contains  C3gIl49NOi2  +  Il20;  t>ut  the 
water  of  crystallisation  is  driven  off  below  100°.-^ 

Pseudaconitine  presents  a  close  resemblance  to  aconitine,  both 
in  its  chemical  and  physiological  characters.^  It  is,  however, 
more  soluble  in  alcohol  and  ether  than  the  latter  base,  crystallises 
with  1  aqua,  and  melts  without  darkening  at  a  considerably 
lower  temperature.  The  melting-point  is  about  104°-105°  C, 
but  is  not  well  marked,  fritting  occurring  a  few  degrees  lower. 

When  crystallised  from  ether,  or  a  mixture  of  ether  with  petro- 
leum spirit,  pseudaconitine  forms  transparent  needles  and  sandy 
crystals ;  but  unless  the  evaporation  is  extremely  gradual  the 
base  is  apt  to  separate  as  a  varnish  at  the  upper  edge  of  the 
solution,  and  soon  forms  a  milk-white,  cauliflower-like,  crystalline 
efflorescence. 

Pseudaconitine  and  its  salts  (with  the  exception  of  the  nitrate, 
BNO3  +  3H2O,  and  aurochloride)  crystallise  with  difficulty,  and 
the  crystallisation  is  impeded,  or  wholly  prevented,  by  very  small 
admixtures  of  amorphous  alkaloid  or  other  impurity. 

Pseudaconitine  Aurochloride,  BHAUCI4,  is  distinctly  crystalline 
when  precipitated  from  a  dilute  solution.  After  drying  over 
sulphuric  acid  it  can  be  readily  crystallised  from  boiling  alcohol 
in  minute  needles  only  sparingly  soluble  in  cold  alcohol  and  which 
are  anhydrous  when  air-dried. 

Pseudaconitine  Chloroplatinate  is  soluble  with  moderate  facility 
in  water,  and  hence  is  not  precipitated  except  from  strong  solu- 
tions. The  mercuro-iodide,  BHgIg,  is  amorphous,  white,  and  very 
sparingly  soluble. 

^  Anhydro-pseudaconitine  and  acetyl-anhydro-pseudaconitine  resemble  the 
parent  base  in  crystallising  with  IH.^O. 

2  Pseudaconitine  contains  a  somewhat  different  proportion  of  carbon  from 
the  other  cr3'stalline  aconite  bases,  and  the  aurochloride  contains  a  somewhat 
different  percentage  of  gold,  but  the  best  defined  character  of  pseudaconitine 
is  its  behaviour  on  saponification. 


218  VERATRIC   ACID. 

Pseudaconitine  is  hydrolysed  with  great  facility.  The  mere 
process  of  heating  with  dilute  alcohol  for  the  purpose  of  recrystal- 
lising  it  results  in  the  production  of  a  very  sensible  quantity  of 
veratric  acid  and  pseudaconine  (page  219).  Hence 
only  a  fraction  of  the  alkaloid  used  crystallises  out  on  cooling,  and 
the  mother-liquor  yields  veratric  acid  on  acidifying,  adding  water, 
and  shaking  with  ether.  If  freshly-precipitated  pseudaconitine  be 
boiled  with  ammonia  or  sodium  carbonate  for  a  few  minutes,  and 
the  solution  then  acidulated  and  shaken  with  ether,  a  considerable 
quantity  of  veratric  acid  is  dissolved  out.  When  boiled  under  a 
reflux  condenser  for  some  hours  with  alcoholic  potash,  pseudaconi- 
tine is  entirely  converted  into  veratric  acid  and  pseud- 
aconine or  the  products  of  the  further  decomposition  of  this 
base.  The  proportion  of  veratric  acid  obtained  approximates 
closely  to  the  theoretical  amount  (26'49  per  cent.).^ 

By  heating  pseudaconitine  to  100°  for  some  hours  with  a  strong 
solution  of  tartaric  acid,  it  is  completely  converted  into  a  n  h  y  d  r  o- 
pseudaconitine,  CggH^^NOi^  (page  205),  a  base  which  closely 
resembles  the  parent  alkaloid. 

Veratric  Acid,  CgHioO^,  or  C6H3(OCH3)2.COOH.i  This  body 
has  the  constitution  of  adimethyl-protocatechuic  acid. 
It  melts  at  174°— 175",  and  can  be  sublimed,  but  is  not  volatile  with 
steam.  It  dissolves  in  2100  parts  of  cold  water,  and  in  160  parts 
at  the  boiling-point,  and  crystallises  from  a  concentrated  solution 
at  about  50°  in  anhydrous  needles,  while  crystals  containing  1  aqua 
are  deposited  from  very  dilute  solutions  at  any  lower  temperature. 
Veratric  acid  dissolves  in  alcohol  and  ether,  and  is  readily  extracted 

'  Possibly  pseuJaconitine  is  not  the  only  base  contained  in  A.  ferox 
which  yields  dimethyl-protocatechuic  acid  on  sapoiiiRcation.  W  r  i  g  li  t  and 
Luff  {Jour.  Chcm.  Sop..,  xxxiii.  174),  when  prepaiing  =pui-e  pseudaconitine 
nitrate  by  adding  excess  of  nitric  acid  to  the  solution  of  the  crude  salt, 
obtained  a  nitric  acid  mother-liquor  from  which  no  crystals  could  be  obtained. 
After  dilution  with  water  and  separation  of  the  i>recipitated  resinous  matter, 
sodium  carbonate  formed  a  copious  precipitate  which  was  freely  soluble  in 
ether,  but  which  could  not  be  made  to  crystallise  or  yield  a  crystalline  salt. 
The  base  was  recovered  from  etlier  as  a  varnish,  which  on  saponification 
yielded  about  19  per  cent,  of  dimethyl-protocatechuic  acid,  and  was  not 
destitute  of  physiological  potency,  though  it  produced  far  less  lip-tingling 
than  pseudaconitine,  which  can  be  readily  obtained  jmre  by  taking  advantage 
of  its  very  slight  solubility  in  a  liquid  containing  8  to  10  per  cent,  of  nitric 
acid.  Since  pure  pseudaconitine  yields  26J  per  cent,  of  veratric  acid  on 
saponification,  Alder  Wright  is  of  opinion  that  this  amor{)hous  alkaloid 
probably  consisted  of  about  three-fourths  of  pseudaconitine  and  other 
saponifiable  bases  (possibly  alteration-products  of  pseudaconitine),  and  one- 
fourth  of  non-saponifiable  bases ;  the  amorphous  bases  preventing  the 
crystallisation  of  whatever  pseudaconitine  was  actually  present. 


REACTIONS   OF   PSEUD ACONITINE.  219 

by  the  latter  solvent  from  its  acidulated  aqueous  solution.  It  pro- 
duces no  coloration  with  ferric  chloride.  When  exactly  neutralised 
with  ammonia  it  gives  a  characteristic  gelatinous  silver  salt 
on  addition  of  a  strong  solution  of  silver  nitrate.  When  veratric 
acid  is  fused  with  caustic  potash  and  a  little  water  at  about  250° 
C,  preferably  in  silver,  it  yields  protocatechuic  acid, 
CgH3(OH)2.COOH.  If  the  melt  be  dissolved  in  water,  the  solu- 
tion acidulated  with  hydrochloric  acid,  shaken  with  ether,  and  the 
ether  separated  and  evaporated,  the  solution  of  the  residual  proto- 
catechuic acid  in  warm  water  will  be  coloured  an  intense  bluish 
green  by  ferric  chloride,  the  -colour  changing  to  dark  red  on 
adding  sodium  carbonate  (compare  Part  I.  page  62).  With 
ferrous  sulphate,  a  neutral  solution  of  a  protocatechuate  gives  a 
violet  coloration. 

The  formation  of  protocatechuic  acid  by  fusion  with  caustic  alkali 
forms  a  convenient  test  for  pseudaconitine.  It  is  only  necessary 
to  fuse  the  alkaloid  with  caustic  potash  and  a  little  water  at  about 
250°  in  a  silver  spoon,  acidulate  the  solution  of  the  melt,  extract 
with  ether,  and  test  the  ethereal  residue  with  ferric  chloride. 

Other  reactions  of  pseudaconitine  dependent  on  the  veratroyl- 
group  are  the  following : — If  a  small  quantity  of  the  alkaloid  and 
a  few  drops  of  fuming  nitric  acid  be  evaporated  to  dryness,  a 
yellow  residue  is  obtained,  which  gives  a  beautiful  purple-red 
colour  when  moistened  with  a  solution  of  caustic  potash  in  abso- 
lute alcohol.  If  pseudaconitine  be  heated  with  concentrated 
sulphuric  acid  to  100°,  and  a  drop  or  two  of  a  solution  of  vanadium 
sulphate  added,  a  violet-red  coloration  is  produced. 

Pseud ACONINE,  C27ll4;^NOg,  is  contained  in  the  aqueous  liquid 
obtained  by  saponifying  pseudaconitine  with  alcoholic  potash, 
acidulating,  and  extracting  the  veratric  acid  by  agitation  with 
ether.  It  may  be  recovered  by  concentrating  the  solution,  render- 
ing it  alkaline  by  sodium  carbonate,  and  agitating  with  ether. 
The  base  being  moderately  soluble  in  water,  sodium  carbonate 
produces  no  precipitate  in  dilute  solutions ;  and  under  these  cir- 
cumstances ether  extracts  the  base  very  imperfectly,  but  removes 
certain  bye-products,  and  on  subsequently  concentrating  the  alka- 
line liquid  the  pseudaconine  separates  as  a  resinous  mass.  The 
last  portions  are  readily  obtained  by  evaporating  the  solution  to 
dryness,  and  treating  the  residue  with  ether,  while  any  aconine 
and  colouring-matters  soluble  in  chloroform  will  be  left  undissolved. 

Pseudaconine  is  left  as  a  transparent  resinous  varnish  on  evapo- 
ration of  its  alcoholic  or  ethereal  solution.  On  standing  a  few 
days  the  film  from  ether  becomes  changed  into  a  mass  of  crystal- 
line needles ;  but  this  effect  is  prevented  by  the  presence  of  small 


220  PSEUDACONINE. 

quantities  of  ether,  alcohol,  or  other  foreign  matters.  If  the 
residue  left  on  evaporating  the  ethereal  solution  be  moistened  with 
water  a  portion  of  the  alkaloid  dissolves,  while  the  remainder 
becomes  opaque,  white  and  brittle,  readily  breaking  up  into 
particles  having  a  pseudocrystalline  appearance.  The  formation 
of  this  apparently  crystalline  product  seems  to  be  peculiar  to 
pseudaconine  and  lycoctonine. 

Pseudaconine  dissolves  in  water  to  form  a  solution  which  is 
strongly  alkaline  and  very  bitter,  but  it  produces  no  tingling  of  the 
skin  or  lips,  and  its  poisonous  properties  are  very  feebly  marked. 
The  aqueous  solution  precipitates  silver  nitrate,  the  precipitate 
being  reduced  on  heating.  It  also  reduces  ammonio-nitrate  of 
silver  on  boiling,  but  it  dififers  from  aconine  and  japaconine  in  not 
reducing  hot  Fehling's  solution,  and  by  its  solubility  in  ether. 
None  of  the  salts  of  pseudaconine  have  been  obtained  in  a  crystal- 
line state. 

Japaconitine.     Sesquianhydro-japaconitine. 

C.    T^    N  n     '   nr  n^  '   ^•^'-'•^6"5 

This  base  is  the  crystalline  alkaloid  of  Japanese  aconite  root.^ 
It  was  first  isolated  by  Paul  and  Kingzett  {Year-Book 
Pharm.,  1877,  469),  who  ascribed  to  it  the  formula  CggH^gNOg. 
Lubbe  believes  it  to  be  identical  with  aconitine  from  A. 
Napellus,  and  to  have  the  formula  CggH^^NOig.  The  formula 
CggHgglSrgOgi  is  due  to  Wright  and  Luff  {Jour.  Gh&in.  Soc, 
XXXV.  387;  Yearbook  Pharm.,  1878,  490),  who  showed  it  to 
form  crystallisable  salts,  and  to  be  readily  saponified  with  produc- 
tion of  benzoic  acid.  As  the  alkaloid  can  be  extracted  from 
Japanese  aconite  root  by  alcohol  alone,  without  the  use  of  acid  of 
any  kind,  it  seems  certain  that  the  base  has  really  the  curious 
constitution  attributed  to  it,  or  else  that  the  hypothetical  parent- 
base  of  the  formula  C33H47NO12,  or  €261139^^07(011)3.0711502, 
suffers  dehydration  by  the  mere  process  of  concentrating  its 
alcoholic  solution. 

Japaconitine  is  readily  obtained  in  long  rhombic  crystals,  and 

^  At  least  two  distinct  species  of  aconite  are  to  be  met  with  in  the  Japanese 
markets.  Much  of  the  root  imported  to  England  is  said  to  have  been  steeped 
in  salt  and  vinegar,  and  then  dried  in  wood-ashes  and  the  sun,  to  protect  it 
against  decay  and  the  ravages  of  insects.  In  a  root  so  treated,  the  alkaloid 
would  be  liable  to  be  materially  modified.  (On  "  Japanese  Aconite  Root,"  see 
Pharm,Jour.,  [3],  x.  149,  1020;  xi.  149,  351,  1021,  1041.) 


JAPACONITINE.  221 

forms  a  crystallisable  nitrate,  hydrochloride  and  hydrobromide. 
These  salts  are  readily  obtained  crystalline  by  adding  the  dilute 
acid  to  a  powdered  crystal  of  the  alkaloid  contained  in  a  watch- 
glass,  and  stirring  the  mixture.  Solution  to  a  clear  fluid  at  first 
takes  place,  and  on  further  stirring  a  crystalline  magma  is  formed, 
just  as  occurs  with  aconitine.  Japaconitine  is  dibasic,  the  salts 
containing  two  molecules  of  acid. 

Japaconitine  presents  the  closest  resemblance  to  aconitine,  both 
in  its  physical  and  chemical  characters.  Its  melting-point, 
184°— 186°,  differs  only  by  a  few  degrees  from  that  of  aconitine. 
The  proportions  of  carbon  and  hydrogen  (compare  page  205),  and 
the  percentage  of  gold  in  the  aurochloride,  are  somewhat  more 
tangible  distinctions,  but  not  of  a  very  practical  character.  The 
crystalline  form,  as  observed  under  the  microscope,  is  a  distinction 
of  value,  aconitine  appearing  in  the  form  of  hexagonal  plates,  and 
japaconitine  in  long  columnar  crystals  (see  illustrations  to  a  paper 
by  Richards  and  Rogers,  Chemist  and  Druggist,  May  18,1889). 

A  method  of  distinguishing  japaconitine  from  aconitine,  and 
even  of  estimating  the  proportions  of  the  two  bases  in  a  mixture, 
might  be  based  on  the  behaviour  of  the  alkaloids  with  benzoic 
anhydride.  According  to  Alder  Wright,  when  aconitine  is 
heated  to  100°  for  eight  hours,  with  twice  its  weight  of  ben- 
zoic anhydride,  it  is  converted  into  dibenzoyl-anhydro- 
a  c  o  n  i  n  e,  0251137^08(0711502)2 ;  whereas  japaconitine,  when  simi- 
larly treated,  yields  a  t e  tra-b enzoy la t ed  derivative, 
^26^39-^^7(^7^6^2)4*  ^^  adding  a  minimum  of  alcohol  to  the 
product,  and  then  agitating  with  aqueous  tartaric  acid  and  a  large 
volume  of  ether,  the  excess  of  benzoic  anhydride  with  benzoic 
acid  and  certain  impurities  are  dissolved  by  the  ether,  while  the 
separated  aqueous  liquid,  when  rendered  alkaline,  yields  to  ether 
the  benzoylated  alkaloids,  which  can  be  weighed  after  evaporating 
the  solvent.  On  saponifying  this  product  with  alcoholic  potash 
(page  204),  the  aconitine  derivative  will  yield  33*40  per  cent,  of 
benzoic  acid,  while  the  benzoylated  japaconitine  will  give 
50 '7 8  per  cent,  of  the  same  body. 

Japaconitine  forms  no  anhydro-base  when  heated  with  aqueous 
tartaric  acid. 

Japaconine,  CggH^jNOjo,  closely  resembles  aconine  (page  214), 
and  can  only  be  distinguished  therefrom  by  elementary  analysis. 

Picraconitine.    C31H45NO10. 

This  base  was  isolated  by  T.  B.  Groves,  together  with  aconi- 
tine, from  a  parcel  of  German  roots  purchased  in  1874  as  those  of 
A,  Napellus;   but  it  appears  doubtful  whether  there  was  not  a 


222  PICRACONITINE. 

large  admixture  of  some  other  species,  or  whether  the  roots  were 
not  of  abnormal  character  from  some  peculiarity  of  soil  or  climate. 
It  has  never  been  met  with  again,  unless,  as  is  not  improbable, 
the  bitter  alkaloid  of  A,  paniculatum  consists  of  picraconitine. 
In  any  case,  the  possible  presence  of  picraconitine  in  aconite  root 
must  not  be  ignored  ;  for,  while  the  alkaloid  resembles  aconitine  in 
yielding  benzoic  acid  on  saponification,  it  does  not  produce  the 
lip-tingling  so  characteristic  of  the  latter  base,  and  is  practically 
inert  physiologically,  half-grain  doses  having  been  taken  internally 
without  the  production  of  any  marked  symptoms. 

Picraconitine  is  a  bitter,  amorphous  resin,  not  fusible  at  100°. 
The  dilute  solutions  of  its  salts  are  not  precipitated  by  ammonia, 
or  caustic  or  carbonated  fixed  alkaloids,  except  on  the  application 
of  heat,  when  the  alkaloid  separates  as  a  thick  coagulum  fusible  in 
boiling  water.     Picraconitine  is  soluble  in  ether  and  cliloroform. 

Picraconitine  forms  crystallisable  salts.  The  hydrochloride 
crystallises  readily  from  hot  solutions  in  fine  needles.  A 
moderately  strong  solution  of  picraconitine  hydrochloride,  if  satu- 
rated with  ammonium  chloride,  becomes  turbid  on  warming  from 
a  precipitate  of  the  alkaloidal  salt,  which,  on  continuing  the  heat, 
is  wholly  deposited  in  fine  needles.  The  test  is  also  applicable 
to  the  nitrate,  and  probably  to  other  salts  of  the  alkaloid. 

Picraconitine  gives  no  colour-reactions  with  the  usual  reagents. 
Its  solutions  are  precipitated  by  tannin  and  Mayer's  solution. 
The  chloroplatinate  is  readily  soluble,  and  the  aurochloride  forms 
a  canary-yellow  precipitate,  not  perceptibly  crystalline,  and  exceed- 
ingly sparingly  soluble  in  water. 

When  boiled  with  alcoholic  potash,  picraconitine  is  saponi- 
fied with  formation  of  benzoic  acid  and  picraconine, 
Co^H^jNOg,  an  amorphous  base  nearly  insoluble  in  ether,  forming 
amorphous  salts,  and  otherwise  presenting  the  closest  resemblance 
to  aconine  (compare  footnote  on  page  216). 

Lyaconitine  and  Myoctonine. 

The  root  of  Aconitum  lycoctonum,  a  species  of  aconite  growing 
in  the  Alps  and  Himalayas,  bearing  yellow  flowers,  has  been  found 
to  contain  two  alkaloids  which  differ  from  the  bases  isolated 
from  other  aconites.  So  far,  the  products  of  the  decomposition  of 
these  bases  by  alkalies  have  not  been  fully  studied,  and  some 
obscurity  rests  on  other  of  their  characters. 

For  the  extraction  of  the  bases  of  A.  lycoctonum^  Dragen- 
dorff  and  Spohn  {Pharm.  Jour.^  [3],  xv.  104)  exhaust  the 
roots  with  alcohol  acidulated  with  tartaric  acid.  The  tincture 
is  concentrated,  mixed  with  water,  filtered,  and  repeatedly  agitated 


LYACONITINE.  223 

with  ether  while  still  acid.  The  ether  removed  traces  of  an  acid 
resembling  protocatechuic  acid,  but  no  benzoic  acid  could  be 
detected.  The  liquor  separated  from  the  ether  was  treated  with 
sodium  bicarbonate  and  extracted  with  ether,  which  removed 
lyaconitine  (1*13  per  cent.).  Subsequent  agitation  with 
chloroform  removed  the  remainder  of  the  lyaconitine,  together 
with  myoctonine  (0'8  per  cent.).  The  successive  treatment 
with  ether  and  chloroform  removed  all  but  traces  of  alkaloid  from 
the  solution.     Neither  base  could  be  obtained  crystallised. 

Lyaconitine^  was  obtained,  after  further  purification  by 
ether  of  the  base  extracted  as  above,  as  a  pale  yellow  resinous 
substance,  yielding  a  white  powder,  and  completely  soluble  in 
dilute  acids  After  drying  in  vacuo,  the  base  begins  to  melt  at 
111°'7,  and  is  completely  fused  at  114°'8  (corrected),  with  partial 
decomposition.  It  is  sparingly  soluble  in  water ;  very  readily  in 
absolute  alcohol,  chloroform,  carbon  disulphide  and  benzene ;  less 
readily  in  ether ;  and  practically  insoluble  in  petroleum  spirit.  A 
10  per  cent,  solution  of  the  base  in  alcohol  shows  a  dextro-rota- 
tion,  Sd= +31°"5.  An  aqueous  solution  of  the  nitrate  shows 
S,=  +  19°-4. 

The  formula  ascribed  to  lyaconitine  by  Dragendorff  and  Spohn 
isC2vH3,N206  +  2H20. 

None  of  the  salts  of  lyaconitine  have  been  obtained  crystallised. 
The  nitrate  can  be  obtained  and  purified  by  dissolving  the  base  in 
ether,  and  cautiously  adding  nitric  acid  mixed  with  ether.  The 
nitrate  is  precipitated,  the  first  fraction  carrying  down  any  colouring- 
matter  contained  in  the  solution. 

With-^strong  sulphuric  acid,  lyaconitine  gives  a  reddish  brown 
coloration,  and  with  syrupy  phosphoric  acid  a  violet  coloration 
on  warming.  When  treated  with  a  mixture  of  8  c.c.  of  water,  6 
of  strong  sulphuric  acid,  and  0'3  of  sodium  selenate,  lyaconitine  is 
coloured  a  rose  or  pale  reddish  violet — a  reaction  which  is  not 
exhibited  by  the  bases  from  other  species  of  aconite. 

Lyaconitine  is  incompletely  precipitated  by  caustic  potash, 
alkaline  carbonates  and  ammonia.  Strong  caustic  alkalies  partially 
decompose  it.  Thus,  when  warmed  for  a  few  minutes  to  a  tem- 
perature of  35°  C.  with  a  4  per  cent,  solution  of  caustic  soda, 
lyaconitine  dissolves,  and  crystalline  lyaconine  separates  from 
the  liquid,  and  may  be  extracted  by  ether.  By  agitation  with  chloro- 
form a  second  base  can  be  extracted,  while  lycoctonic 
acid  and  a  resinous  substance  remain  dissolved.^ 

*  Also  called  lycaconitine. 

2  Lyaconitine  and  its  salts  being  amorphous,  their  composition  cannot  be 
considered  well-estahlislied.     The  formula  attributed  to  lyaconine  is  remark- 


224  LYCOCTONINE. 

Lyaconine,  C27H4yN207  + 1  i  aqua,  is  apparently  ideutical  with 
the  base  described  by  H  U  b  s  c  h  m  a  n  n  under  the  name  of  lycoc- 
tonine}  It  melts  at  90°-92°,  has  an  alkaline  reaction,  and  an 
optical  activity  of  Sd=  +46°'4.  It  is  very  soluble  in  alcohol  and 
chloroform,  less  readily  in  ether  and  benzene,  and  dissolves  in 
about  250  parts  of  water.  Its  solution  has  an  alkaline  reaction, 
exhibits  a  fine  blue  fluorescence,  is  coloured  purple  by  chlorine- 
water,  and  is  precipitated  by  the  ordinary  alkaloidal  reagents. 

The  aurochloride,  platinochloride  and  nitrate  of  the  base  have 
been  prepared. 

AcoLYCTiNE,  a  base  described  by  H  ii  b  s  c  h  m  a  n  n,  is  probably 

able  in  containing  an  uneven  number  of  atoms  of  hydrogen.  Correcting  it  to 
contain  H4g,  and  attributing  to  lyaconitine  the  formula  CayHgoNgOg,  the  prin- 
cipal reaction  occuriing  by  its  reaction  with  soda  would  be  : — 

2C27H33N20a + 2H2O  -  C27H48N2O7  +  C07H18N2O7 . 

^  A  specimen  of  "  ly  co  ct  onine,"  from  A.  lycoctonum,  presented  by 
H  ii  b  s  c  h  m  a  n  n  to  F 1  ii  c  k  i  g  e  r,  is  described  by  the  latter  chemist  (  Year- 
BooTc  Pharm. ,  1870,  page  99,  from  Archiv.  der  Pharm.,  cxci.)  as  being  crystal- 
lised in  perfectly  white  and  distinct  prisms  and  needles,  melting  at  98°-104*' 
without  darkening,  and  forming  a  transparent  glassy  mass  on  cooling.  On 
contact  with  water  this  mass  at  once  crystallised.  The  base  was  soluble  in 
alcohol,  ether,  chloroform,  amylic  alcohol,  petroleum  spirit  and  carbon 
disalphide.  By  rapid  evaporation  from  these  solvents,  the  alkaloid  formed  a 
varnish  which  crystallised  on  contact  with  water  ;  but  by  slow  evaporation 
crystalline  tufts  were  obtained.  The  aqueous  solution  of  the  base  had  an 
alkaline  reaction  and  intensely  bitter  taste.  The  physiological  effects  of 
lycoctonine  were  found  to  differ  from  those  of  the  other  aconite  bases  both  in 
degree  and  kind.  As  a  poison,  lycoctonine  was  found  much  less  energetic  than 
aconitine.  ^lercuric  chloride,  platinic  chloride,  phosphomolybdic  acid  and 
iodide  of  potassium  produced  no  precipitate  in  solutions  of  lycoctonine  salts  ; 
but  the  base  was  thrown  down  by  tannin,  iodised  potassium  iodide,  bromine- 
water  (which  gave  a  precipitate  of  microscopic  needles)  and  the  double  iodides 
of  potassium  with  mercury,  bismuth  and  cadmium.  Potassium  mercuro-iodide 
threw  down  a  precipitate  which  crystallised  on  standing,  In  solutions  of  1  in 
8000  no  immediate  effect  was  produced,  but  in  about  fifteen  minutes  beautiful 
crystals  made  their  appearance  ;  and  in  a  dilution  of  1  in  20,000  they  were 
formed  in  twenty-four  hours.  The  precipitate  was  readily  soluble  in  alcohol, 
and  crystallised  very  beautifully  from  the  solution.  Mercuro-bromide  of 
potassium  does  not  affect  lycoctonine  solutions  unless  very  concentrated,  but 
both  it  and  the  mercuro-iodide  throw  down  amorphous  preci{)itates  from  solu- 
tions of  aconitine,  and  do  not  affect  narcotine  solutions.  With  potassio-iodide 
of  bismuth  lycoctonine  formed  a  precipitate  in  a  dilution  of  1  in  40,000. 
Sulphuric,  nitric  and  phosphoric  acids  produced  no  colour-reactions.  The 
nitrate  of  lycoctonine  crystallised  in  tables,  the  sulphate  in  prisms.  Solutions 
of  the  salts  were  not  precipitated  by  caustic  or  carbonated  alkalies,  though  the 
base  itself  was  not  notably  soluble  in  alkalies. 


MYOCTONINE.  225 

identical  with  the  second  base  extracted  by  Dragendorff  and 
S  p  0  h  n  from  the  product  of  the  action  of  caustic  alkali  on 
lyaconitine.  It  is  probably  a  product  of  the  further  action  of  the 
alkali  on  lyaconine  (lycoctonine).  It  is  described  as  a  white 
powder,  soluble  in  water,  alcohol  and  chloroform,  but  insoluble  in 
ether.  It  forms  white  precipitates  with  tannin  and  lead  acetate, 
and  a  yellow  with  auric  chloride.  Its  sulphate  forms  a  white 
precipitate  with  ammonium  molybdate.  Acolyctine  produces 
physiological  effects  similar  to  those  of  myoctonine,  but  less 
powerful. 

Lycoctonic  Acid,  C27lIjgN207,  produced  by  the  action  of  alkalies 
on  lyaconitine  (or  by  heating  the  base  with  water  or  dilute  acid  in 
a  sealed  tube),  is  crystallisable,  and  melts  at  146°— 148°.  It  is 
sparingly  soluble  in  water,  moderately  in  ether,  and  readily  in 
alcohol  and  chloroform. 

Myoctonine,  according  to  Dragendorff  and  S p o h n,  has 
the  formula  C27H30N2O8  +  5H2O,  while  Einberg  regards  it  as 
C4oH5gN20i2  +  5H20,  the  water  being  lost  on  drying  in  a  current 
of  air  at  60°.  It  is  amorphous,  has  a  bitter  but  not  pungent  or 
tingling  taste,  melts  at  143°-144°,  and  is  dextro-rotatory.  (S^ 
for  the  alkaloid  in  10  per  cent,  solution  in  alcohol  =  -|-29°*5  ;  of 
the  nitrate  in  aqueous  solution  21°'2.)  It  is  difficultly  soluble  in 
water,  but  very  soluble  in  alcohol,  amylic  alcohol,  acetic  ether, 
chloroform,  benzene,  and  carbon  disulphide.  Ether  and  petroleum 
spirit  only  dissolve  traces  of  it.  The  salts  refuse  to  crystallise. 
jMyoctonine  is  precipitated  by  most  of  the  general  reagents  for 
alkaloids  in  solutions  not  too  dilute,  and  may  be  titrated  by 
Mayer's  solution  (1  c.c.  =  0*0176  of  alkaloid). 

An  aqueous  solution  of  myoctonine  hydrochloride  gives  with 
excess  of  bromine-water  an  amorphous,  very  sparingly  soluble 
precipitate,  said  to  contain  C^qK^^Bt^N 20-^2- 

If  a  fragment  of  myoctonine  be  moistened  with  fuming  nitric 
acid  and  dried,  the  residue  acquires  a  reddish  brown  colour  on 
adding  a  drop  of  alcoholic  potash  (compare  atropine). 

On  heating  to  100°  with  a  4  per  cent,  solution  of  soda,  myoc- 
tonine is  stated  by  Dragendorff  and  Spohn  to  behave 
similarly  to  lyaconitine,  yielding  lycoctonic  acid,  lya- 
conine, a  base  resembling  acolyctine,  and  a  fourth  product 
of  indefinite  nature.  The  behaviour  of  myoctonine  with  caustic 
alkali  has  also  been  studied  by  F.  Einberg  (Inaugural 
Dissertation,  Dorpat,  1887).  When  myoctonine  was  heated  on 
the  water-bath  with  4  per  cent,  caustic  soda  solution,  a  spar- 
ingly soluble  basic  decomposition-product  separated  in  crystals, 
which,  when  filtered  off  and  purified,  amounted  to  24  per  cent,  of 

VOL.  III.  PART  II.  P 


226  MYOCTONINE. 

the  myoctonine  taken.^  The  filtrate  was  brownish,  and  had  a 
peculiar  pungent  smell.  When  acidulated  and  shaken  with  ether, 
a  body  exhibiting  a  blue  fluorescence  was  extracted ;  and  on 
evaporation  30'45  of  a  brownish  serai-crystalline  residue  was 
obtained,  in  which  Einberg  recognised  benzoic  acid  as  the 
main  constituent.  The  acid  liquid,  when  rendered  alkaline  with 
sodium  carbonate,  yielded  11 '84  per  cent,  to  ether  and  an  additional 
8"89  per  cent,  to  chloroform,  both  solvents  leaving  amorphous 
yellowish  brown  residues  on  evaporation. 

According  to  S  a  1  m  o  n  o  w  i  t  z,  myoctonine  is  a  powerful  poison 
resembling  curare  in  its  action,  and  acting  most  energetically  when 
introduced  directly  into  the  circulation.  The  subcutaneous  injec- 
tion of  0'075  gramme  of  the  nitrate  produced  distinct  toxic 
symptoms  in  cats,  and  the  injection  of  0*100  gramme  always 
caused  death  in  about  half  an  hour.  Mice  were  killed  in  three 
minutes  by  a  dose  of  0*001  gramme. 

Atisine.     C^gH^^NgOg  -,  or  perhaps  Cc^^^^^^O^P' 
Atisine  is  the  characteristic  alkaloid  of  Aconitum  lieterophyllum, 

a  species  of  aconite  which  grows  in  the  more  temperate  parts  of 

the   Himalayas.^     The   atisine  exists  in  the  root  in  combination 

with  aconitic  acid. 

Atisine  is  described  as   white  and    uncrystallisable,   becoming 

coloured  and  resinous  on  exposure  to  air,  and  melting  at  85°.     It 

^  To  this  base,  after  drying  at  80*,  Einberg  ascribed  the  formula  C24H3gNOB, 
and  considered  it  identical  with  Hiibschmann's  lycoctonine.  It  melted  at  94°, 
and  had  a  rotation  in  absolute  alcohol  of  +38°*9.  It  became  amorphous  when 
melted,  reassuming  the  crystalline  form  on  contact  with  steam.  It  dissolved 
in  about  250  parts  of  water,  4  of  absolute  alcohol,  3  "4  of  chloroform,  55  of 
ether,  and  63  of  benzene,  which  characters  agree  with  those  ascribed  by  Hiibsch- 
raann  to  lycoctonine.  The  base  formed  a  crystalline  nitrate,  very  hygroscopic 
and  easily  soluble  in  water.  Strong  sulphuric  acid  coloured  the  base  bright 
yellow,  changed  to  a  fine  orange  on  warming. 

^  The  formula  C46H74N2O5  was  deduced  by  the  discoverer  of  atisine, 
J.  Broughton,  from  an  analysis  of  the  platinum  salt.  It  was  confirmed  (?) 
by  Wasowicz  by  carbon  and  hydrogen  determinations  on  the  free  base  and 
by  analyses,  the  nature  of  which  are  not  stated,  of  the  hydriodide,  which  led 
to  the  formula  C48H74N2O4,  HI  +  HoO  {sic).  On  the  other  hand,  C.  R.  A 1  d  e  r 
Wright  found  that  the  formula  CgoHgiNOg  agreed  better  with  determinations 
of  carbon,  hydrogen,  nitrogen  and  gold  in  the  aurochloride  of  the  base  ex- 
tracted by  him  from  a  small  batch  of  Atis  roots  (  Year-Book  Pharm.,  1879,  422). 

'  A.  hsterophyllum  bears  flowers  which  are  either  wholly  blue,  or  of  a  dirty 
yellow  with  purple  stripes.  In  the  bazaars  of  India  the  root  is  sold  commonly 
as  a  popular  bitter  tonic,  under  the  name  of  Atis  or  Atees  root.  The  plant  and 
root  of  A.  heterophyllum  have  been  fully  described  and  figured  by  Wasowicz 
{Pharm.  Jour.,  [3],  x.  301,  341,  463).     The  root  is  apparently  identical  with 


ATISINE.  227 

has  a  strong,  pure,  hitter  taste,  without  any  acrid  or  burning  after- 
taste, and  is  not  poisonous.  The  alkaloid  is  but  little  soluble  in 
water  or  dilute  spirit,  but  readily  in  strong  alcohol,  ether  and 
benzene.  When  the  alcoholic  solution  is  strongly  diluted  with 
water,  the  greater  part  of  the  alkaloid  is  precipitated,  and  the 
liquid  froths  strongly  on  agitation. 

According  to  W  a  s  o  w  i  c  z,  strong  sulphuric  acid  colours  atisine 
a  faint  violet,  which  changes  to  red  and  dirty  brown.  Nitric  acid 
produces  a  brown,  sulphuric  acid  a  red,  and  potassium  bichromate  a 
green  coloration,  with  a  distinct  reddish  violet  zone.  Shimoyama 
(Pharm.  Jour.,  [3],  xxvi.  86)  obtained  with  some  of  the  alkaloid 
prepared  by  Wasowicz  a  yellowish  solution  in  concentrated 
sulphuric  acid,  gradually  changing  to  a  magnificent  purple-red, 
which  lasted  several  days,  but  became  momentarily  violet  on  adding 
a  drop  of  water.  No  coloration  was  produced  by  nitric  or  hydro- 
chloric acid.  Phosphoric  acid  dissolved  the  alkaloid  without 
colour,  but  on  warming  the  solution  for  some  minutes  it  began  to 
show  a  yellowish  violet  colour.  Sulphuric  acid  and  sugar  produced 
at  first  a  yellowish  colour,  which,  after  a  few  minutes,  changed  to 
yellowish  red  and  then  to  carmine-red. 

The  sulphate,  nitrate  and  acetate  of  atisine  do  not  appear  to 
crystallise,  but  the  hydrochloride,  hydrobromide  and  hydriodide 
are  crystallisable  and  sparingly  soluble  salts. 

Amrnohia  precipitates  atisine  from  the  solutions  of  its  salts  in 
white  flocks.  Tannin  gives  a  yellowish  brown  precipitate,  and 
potassio-mercuric  iodide  a  white  precipitate,  dissolving  in  alcohol 
to  a  solution  which  leaves  a  distinctly  crystalline  mass  on 
evaporation. 

Atisine  Hydriodide,  BHI-f-HgO.  When  the  precipitate  of 
atisine  mercuro-iodide  is  suspended  in  water,  and  decomposed  by 
sulphuretted  hydrogen,  shining  pearly  scales  of  atisine  hydriodide 
are  deposited.  These  dissolve  in  a  sufficiency  of  hot  water,  and 
are  deposited  again  on  cooling.^  The  salt  dissolves  in  318  parts 
of  water  at  20°,  and  is  very  sparingly  soluble  in  alcohol. 

Atisine   Hydrochloride    is    a    white    crystalline   powder,    more 

"wakmali"  or  "bikmah,"  the  former  of  which  is  regarded  by  Royle  as  the 
tuber  of  the  poisonous  A.  palmatum,  a  view  which  Shimoyama  {Pharm. 
Jour.,  [3],  xvi.  86)  regards  as  highly  improbable.  In  anatomical  characters, 
wakmah  and  atis  roots  exactly  correspond,  and  they  yield  the  same  alkaloid. 

^  When  the  mother-liquor  is  concentrated  to  a  point  at  which  no  more  crystals- 
are  deposited  on  cooling,  it  still  yields  a  precipitate  with  potassio-iodide  of 
mercury,  the  alcoholic  solution  of  which  leaves  an  un crystallisable  residue  on 
evaporation.  This  behaviour  appears  to  point  towards  the  presence  of  a 
second  alkaloid. 


228  ASSAY   OF  ACONITE   ROOT. 

soluble  in  water  than  the  hydriodide.     It  has  a  strong  bitter  taste, 
but  is  free  from  the  disagreeable  after-taste  of  the  latter  salt. 

Assay  of  Aconite  and  its  Preparations. 

The  analytical  assay  and  valuation  of  the  alkaloids  and  other 
preparations  of  aconite  yield  very  unsatisfactory  results,  not  so 
much  from  the  difficulty  of  isolating  and  identifying  the  alkaloids 
present,  as  from  the  uncertainty  which  exists  between  the  amount 
and  nature  of  the  alkaloids  obtained,  and  the  physiological  activity 
of  the  preparations  yielding  them.  The  most  conflicting  state- 
ments have  been  made  respecting  the  relative  activity  of  the  actual 
alkaloids,  even  when  these  have  been  isolated  in  a  crystalline  con- 
dition ;  but  the  evidence  of  later  observers,  especially  Mandelin 
{Pharm.  Jour.,  [3],  xvi.  781),  tends  to  show  that  the  experiences 
of  the  earlier  experimenters  were  due  in  part  to  the  use  of 
preparations  containing  a  notable  proportion  of  amorphous  and 
relatively  inert  bases,  to  an  insufficient  number  of  physiological 
experiments,  and  ignorance  of  the  fact  that  the  age,  sex,  and  general 
condition  of  an  animal,  besides  its  individual  idiosyncrasy,  materially 
afiPects  its  susceptibility  to  the  poison.  Man,  again,  is  evidently 
more  sensitive  to  aconitine  than  cats  or  dogs,  and  apparently 
old  people  are  more  susceptible  than  young  (compare  page  236). 

As  a  means  of  judging  of  the  quality  of  aconite  root,  E.  R. 
Squibb  {Ephemeris,  i.  125)  recommends  that  a  thin  slice  of 
definite  section  should  be  chewed  in  the  lips,  and  the  strength  and 
length  of  the  tingling  sensation  noted.  A.  B.  Lyons  has 
modified  this  test  by  employing  one  drop  of  a  10  per  cent,  tincture 
of  the  root.  For  liquid  preparations,  Squibb  places  1  fluid 
drachm  of  a  solution  of  the  drug  in  the  anterior  part  of  the  mouth, 
previously  rinsed  with  water,  and  holds  it  there  for  one  minute, 
when  the  mouth  is  emptied  and  again  rinsed.  A  tenth  of  a 
minim  of  a  1  in  1  fluid  extract,  when  examined  in  this  way, 
should  produce  a  distinct  aconite  sensation  not  amounting  to 
tingling,  but  very  suggestive  of  it,  and  continuing  more  or  less  for 
fifteen  to  thirty  minutes. 

The  total  alkaloids  contained  in  aconite  root  can  be  ascertained 
by  processes  substantially  identical  with  those  employed  in  preparing 
aconitine.  The  details  of  manipulation  to  be  preferred  have  been 
investigated  by  E.  H.  F  a  r  r  and  R.  Wright  (Pharm.  Jour., 
[3],  xxi.  1037).  They  recommend  the  exhaustion  of  the  root  by 
continuous  percolation.  One  ounce  (or  20  grammes)  of  the  drug, 
reduced  to  coarse  powder,  is  moistened  with  spirit  of  0*890 
specific  gravity  (which  is  preferable  to  either  stronger  or  weaker 
alcohol),  and  packed  in  a  conical  percolator,  when  more  of  the 


TINCTURE  OF  ACONITE. 


229 


menstruum  is  gradually  added,  and  percolation  allowed  to  proceed 
slowly  but  continuously  until  8  fluid  ounces  (or  160  c.c.)  of 
percolate  has  been  obtained. 

The  tincture  of  aconite  thus  obtained  is  then  evaporated  over 
hot  water  to  a  low  bulk,  till  all  the  alcohol  is  driven  off.  The 
residual  liquid  is  allowed  to  cool ;  some  water  added,  if  necessary,  to 
reduce  the  viscosity;  and  then  treated  with  15  c.c.  of  decinormal 
sulphuric  acid.  The  liquid  is  then  filtered  ;  the  precipitate  washed 
with  acidulated  water ;  and  the  filtrate  shaken  twice  with  chloro- 
form to  remove  colouring-matter.  The  separated  chloroform  is 
shaken  with  acidulated  water  to  remove  adherent  traces  of  alkaloid, 
the  aqueous  liquid  being  added  to  the  main  quantity.  The 
alkaloidal  solution  is  then  treated  with  a  slight  excess  of  potassium 
carbonate,  and  the  alkaloids  extracted  by  two  agitations  with 
chloroform,  using  30  to  40  c.c.  each  time.  The  separated  chloro- 
formic  solution  is  washed  with  a  little  distilled  water,  and  then 
evaporated  or  distilled  over  hot  water,  the  residual  alkaloids  being 
dried  at  1 00°  C.  till  constant  in  weight.  The  alkaloids  thus  obtained 
are  almost  white,  and  vitreous  in  appearance.  Prolonged  exposure 
at  the  boiling-point  of  water  causes  a  slight  darkening  in  colour.^ 

The  following  proportions  of  total  alkaloids  were  obtained  by 
F  a  r  r  and.  Wright  by  the  above  process.  No.  1  sample  was  a 
root  of  Japanese  origin ;  one  sample  was  of  unknown  origin ;  and 
the  rest  were  roots  of  A.  Napellus  grown  in  Germany.  The 
extractive  matter  shown  in  the  table  was  determined  by  evaporating 
a  measured  quantity  of  the  tincture  over  hot  water,  and  drying 
the  residue  at  100°. 


Sample. 


No.  1  (Japanese),  . 

No.  2, 

No.  3, 

No.  4 

No.  5 

No.  6 

No.  i. 

No,  8 

No.  9 

No.  lo: 

No.  11 

Average, 


From  100  o.a  of  Tincture. 


Alkaloids. 


•073 


•050 
•063 
•045 
•070 
•086 
•082 
•050 
055 

•062 


Extract. 


2-89 
2-92 
4-08 
3-64 
318 
3^28 
1-44 
3^40 
3^82 
2  •46 

312 


From  lOO  Grammes 
OP  Root. 


Alkaloids. 


•584 
•368 
•528 
•400 
•504 
•360 
•560 
•388 
•656 
•400 
•440 

•496 


These  results  show  a  much  better  yield  of  total  alkaloids  than 

^  The  foregoing  process  is,   of    course,    directly  applicable  to   commercial 
tincture  and  liniment  of  aconite.     The  extract  should  be  treated  with  alcohol, 


230  YIELD   OF   ACONITE   ALKALOIDS. 

was  obtained  from  the  root  of  A.  Napellus  by  C.  R.  Alder  Wright, 
wlio  extracted  only  '07  per  cent.,  of  which  '03  per  cent,  was 
obtained  in  a  distinctly  crystalline  form.^  From  the  root  of 
Japanese  aconite,  Alder  Wright  obtained  0*25  per  cent,  of 
total  alkaloids,  of  which  0'08  was  crystallised.  H  a  g  e  r  found  from 
0'05  to  0*40  of  cry stalli sable  alkaloid,  with  a  total  yield  of  0'6-i 
to  1*25  per  cent.  W.  Procter  found  0'46  per  cent,  of  total 
alkaloid  in  American  root  {A.  Napellus),  but  only  0'20  in  root  of 
German  growth.  From  the  flowers  of  A.  ^;am'cz^Za^Mm,  E.  L. 
Cleaver  extracted  0'9  per  cent,  of  total  alkaloids  (bitter,  not 
tingling) ;  from  the  leaves  O'l  per  cent. ;  and  from  the  extract  of 
the  whole  ])lant  0'3  per  cent.  Richards  and  Rogers 
{Chemist  and  Druggist,  Feb.  14,  1891)  extracted  0*57  per  cent,  of 
crystallised  aconitine  from  dry  Japanese  aconite  root;  0*14  per 
cent,  from  dry  root  of  A.  Napellus  ;  and  0'71  per  cent,  from  fresli 
roots  (both  wild  and  cultivated)  of  the  same  species.  These 
results  suggest  a  notable  loss  of  (crystallisable)  alkaloid  during  the 
process  of  drying. 

Ail  the  foregoing  estimations  were  made  by  fairly  reliable 
methods,  and  show  that  the  proportion  of  alkaloids  in  aconite 
varies  widely,  being  probably  largely  affected  by  the  time  of 
collection,  the  age  of  the  plant,  and  possibly  by  the  climate  and 
soil.  The  method  of  extraction  profoundly  affects  the  nature  as 
well  as  the  amount  of  alkaloids  obtained ;  any  heat  or  employment 
of  mineral  acids  tending  to  effect  hydrolysis  of  the  crystalline 
alkaloids  with  formation  of  amorphous  bases. 

A.  B.  Lyons  found  the  moisture  of  aconite  root  to  range  from 
8'2  to  ir2  per  cent.,  and  the  extractive  yielded  to  alcohol  to  vary 
from  9'3  to  19"8  per  cent.  The  alkaloid  from  10  grammes  of  the 
root  required  from  3*7  to  10*8  c.c.  of  ,J  Mayer's  solution  for  its 
precipitation. 

A  striking  example  of  the  effect  of  the  process  of  extraction 
on  the  character  and  proportion  of  the  alkaloids  obtained  is 
afforded  by  the  following  results  of  C.  Schneider  {Archiv 
der  Pharm.y  ccxix.  Xo.  5),  obtained  with  the  same  sample  of 
aconite  root: — 

and  the  liquid  filtered  and  proceeded  with  like  that  percolated  from  the  root 
The  ointment  can  be  treated  similarly.  The  leaves  and  other  parts  of  the 
aconite  p?a?i^  can  be  assayed  in  a  manner  similar  to  that  employed  for  the 
root. 

^  A  still  smaller  yield  of  alkaloid  was  obtained  by  Alder  Wright  and 
Rennie  from  the  fresh  (English)  herb  (flowers,  leaves  and  stalks),  namely, 
about  0'05  per  cent,  calculated  oji  the  dry  herb,  and  of  this  only  a  small 
fractiou  could  be  obtained  crystallised  {Year- Book  Fharm.,  1880,  455). 


EXTKACTION    OF   ACONITE   ALKALOIDS. 


231 


Process  Employed. 

Character  0/ Alkaloid. 

Percentage. 

British  Pharmacopoeia  (1867), 
Morton's,       .... 
Hirzel'8,  .       . 

Wittstein's,    .... 
Hottot  and  Li^gois',     . 
Duquesuel's,  . 

Light  yellow  powder. 

Well-formed,  isolated,  six-sided 

tablets. 
Crystals. 

Well-developed  crystals. 

•002 

•127 

•0046 

•140 

•296 

•339 

The  good  results  obtained  by  Duquesnol's  process  were 
doubtless  due  to  extraction  by  percolation  with  cold  alcohol, 
acidulated  with  tartaric  acid,  while  all  the  others  employ  more  or 
less  heat,  some  with  and  some  without  sulphuric  acid. 

A  solution  of  potassio- iodide  of  mercury  (Mayer's  reagent) 
may  be  employed  for  the  volumetric  determination  of  aconite 
alkaloids  in  acid  solution.  The  difficulty  attending  the  use  of  the 
process  is  the  uncertainty  of  the  factor  to  be  employed  where  there 
is  no  knowledge  of  the  composition  of  the  alkaloid  present.^ 

Mayer's  reagent  may  be  used  for  the  concentration  of  the 
aconite  bases.  The  precipitate  is  filtered  off,  washed,  suspended 
in  water,  and  decomposed  by  a  stream  of  sulphuretted  hydrogen. 
The  filtered  liquid  is  treated  with  an  alkaline  carbonate,  and 
shaken  with  ether  or  chloroform;  the  extracted  base  being  recovered 
by  evaporation  in  the  usual  way.^ 

Where  the  alkaloids  of  aconite  have  been  extracted  and  obtained 
in  a  fairly  pure  condition,  they  may  be  determined  by  titration 
with  standard  acid  and  methyl-orange.  Operating  in  the  manner 
described  on  page  131,  the  author  found  that  very  accurate  deter- 
minations could  be  made.      Thus  30  milligrammes  of  crystallised 

^  By  titration  with  Mayer's  reagent,  Z  i  n  o  f  f  s  k  y  examined  the  aconites 
cultivated  at  Dorpat  in  1871.  Of  the  portions  of  the  plants  above  ground  he 
found  the  flowers  always  richest  and  the  stalks  poorest  in  alkaloid ;  the  lowest 
occuiiying  au  intermediate  place,  and  containing,  when  fresh,  about  80  per 
cent,  of  water,  and  from  0'167  to  0"271  per  cent,  of  alkaloid.  The  highest 
proportion  of  alkaloid  was  0729,  found  in  the  fresh  flowers  (collected  at  the 
end  of  July)  from  A.  Stoerckianum.  By  the  assay,  apparently  by  Mayer's 
solution,  of  entire  aconite  plants  (including  the  roots)  collected  at  Dorpat 
Botanical  Gardens  in  June  1871,  F.  Dragendorff  {Quelques  Drogues 
Actives)  found  proportions  of  alkaloid  ranging  from  0*054  to  0*327  per  cent, 
in  the  fresh  substance  containing  about  80  per  cent,  of  water,  and  from  0"195 
to  0*844  calculated  on  the  dry  material. 

2  In  a  private  communication  to  the  author,  Alder  Wright  states  that 
there  is  some  reason  for  supposing  that  the  crystallisable  bases  are  apt  to  be 
more  or  less  altered  by  this  treatment,  and  rendered  uncrystallisable. 


232  TITKATION   OF   ACONITE   ALKALOIDS. 

aconitine  was  dissolved  in  15  c.c.  of  (neutral)  ether;  3  c.c.  of 
water  containing  a  drop  of  a  j^  per  cent,  solution  of  methyl- 
orange  (previously  rendered  sensibly  pink  by  a  minute  addition  of 
acid)  added;  and  g  hydrochloric  acid  dropped  in  from  an  accurately 
divided  pipette,  shaking  well  after  each  addition,  till  a  permanent 
red  coloration  of  the  aqueous  layer  was  obtained.  Two  experi- 
ments made  in  this  manner  showed  29*9  and  31-0  milligrammes 
of  aconitine,  against  30  taken  ;  while  30  milligrammes  of  japaconi- 
tine  (not  quite  pure)  showed  29-8  by  titration. 

1  C.C.  of  ^  acid  neutralises  12-94  miUigrammes  of  aconitine. 
,,  ,,  10*86  ,,  aconine. 

,,  „  14*14  ,,  pseiidaconitine. 

,,  ,,  10*46  „  pseudaconine. 

„  ,,  12*44  „  japaconitine. 

,,  ,,  10*54  „  japaconine. 

The  determination  of  the  total  alkaloids  of  an  aconite  prepara- 
tion is  in  itself  of  little  value  if  any  as  a  criterion  of  its  activity. 
It  is  rather  the  first  step  in  the  process  of  assay,  the  potency  of  the 
preparation  substantially  depending  on  the  results  subsequently 
obtained.'^ 

^  Where  the  amount  of  material  is  suflBcient  it  is  very  desirable  to  isolate 
the  crystallisable  alkaloid  ;  and  if  this  could  be  eflfected  with  an  approach  to 
quantitative  accuracy,  it  would  probably  furnish  the  most  reliable  criterion  of 
the  physiological  activity  of  the  substance.  In  practice,  however,  very  great 
difficulties  attend  such  a  method  of  examination.  In  the  first  place,  there  is 
always  a  danger  that  the  maximum  yield  of  crystals  may  not  be  obtained,  and 
hence  that  the  activity  of  the  preparation  will  be  seriously  under-estimated. 
But,  apart  from  this  source  of  error,  there  exists  the  grave  difficulty  that  the 
amount  of  substance  which  is  commonly  available,  or  can  be  conveniently 
submitted  to  examination,  yields  a  quantity  of  total  alkaloids  far  too  small  to 
render  any  method  based  on  crystallisation  practically  available. 

In  the  manufacturing  laboratory,  where  comparatively  large  quantities  of 
material  are  available,  a  good  and  simple  method  of  effecting  at  least  a  partial 
separation  of  the  crystallisable  alkaloids,  and  which  has  the  advantage  of  being 
equally  applicable  to  aconitine,  pseudaconitine  and  japaconitine,  is  as  follows  : — 
The  ethereal  residue  is  redissolved  in  ether  in  a  small  beaker.  The  solution  is 
then  stirred  with  a  glass  rod  which  has  been  dipped  in  nitric  acid,  or  with  a 
jupette  from  the  orifice  of  which  the  acid  is  allowed  to  trickle  very  slowly. 
At  each  addition  of  the  acid  a  white  cloud  of  the  alkaloidal  nitrate  will  be 
produced,  which  ceases  to  appear  when  the  acid  has  been  added  in  excess. 
After  standing  a  few  minutes,  all  the  nitrate  formed  collects  as  a  crystalline 
maj>s  on  the  bottom  and  sides  of  the  beaker,  and  the  ether  may  be  poured  off. 
The  nitrate  may  be  purified  by  dissolving  it  in  a  minimum  of  hot  water, 
allowing  the  liquid  to  become  cold,  and  then  adding  nitric  acid,  drop  by  drop, 
with  constant  stirring,   until  no  further  separation  of  crystals  takes  place. 


ASSAY   OF  ACONITE  ALKALOIDS.  233 

The  only  principle  of  assay  hitherto  proposed  for  the  aconite 
alkaloids,  making  any  attempt  to  discriminate  between  them  and 
estimate  the  activity  of  a  mixture,  is  that  based  on  saponification 
of  the  active  bases.  A  method  of  this  kind  was  suggested  by 
Alder  Wright,  who  proved  that  the  saponification  of  aconitine, 
pseudaconitine  and  japaconitine  occurred  with  a  near  approach 
to  quantitative  accuracy  (page  204). 

A  method  of  assay  based  on  the  saponification  of  the  crystallis- 
able  alkaloids  of  aconite,  has  the  great  advantage  of  distinguishing 
sharply  between  the  three  principal  poisonous  aconite  bases  on  the 
one  hand,  and  the  comparatively  inactive  products  of  their  decom- 
position on  the  other.  As  it  is  generally  accepted  that  aconine 
has  only  g^^  of  the  physiological  activity  of  aconitine,  and  that 
japaconine  and  pseudaconine  bear  a  similar  relation  to  their  respec- 
tive parent  alkaloids,  it  may  be  assumed  that  the  activity  of  a 
mixture  of  aconite  alkaloids  is  substantially  represented  by  the 
proportion  of  crystallisable  saponifiable  base  present;^  and,  there- 
fore, the  determination  of  the  latter  with  reasonable  accuracy  is  a 
considerable  advance  towards  the  solution  of  the  problem  of  the 
assay  of  aconite  preparations.^ 

The  salt  is  then  drained  and  pressed  between  filter-paper,  dissolved  in  warm 
water,  sodium  bicarbonate  added,  the  liberated  alkaloid  extracted  with  ether, 
the  ethereal  solution  separated  and  evaporated,  and  the  residue  weighed. 

^  It  is  true  that  the  bitter  non-poisonous  alkaloid,  ]jicraconitine,  is  saponi- 
fiable;  but  it  has  only  been  met  with  on  one  occasion  (1874,  see  page  221), 
unless  it  is  identical  with  the  imperfectly-examined  bitter  alkaloid  obtained 
by  E.  L.  Cleaver  from  the  root  of  A.  paniculatum.  Lyaconitine  and 
myoctonine,  the  amorphous  alkaloids  of  A.  lycoctonum,  are  saponifiable,  but 
are  of  no  practical  interest.  Both  Alder  Wright  and  A.  Jiirgens 
found  a  small  quantity  of  an  amorphous  saponifiable  alkaloid  in  A.  Napellus^ 
and  J.  C.  Umney  has  stated  that  unpublished  experiments  of  his  confirm 
this  conclusion.  But  neither  Wright  nor  Jiirgens  succeeded  in  preparing 
the  base  in  question  quite  free  from  aconitine,  and  the  quantity  isolated  was 
too  small  to  allow  of  complete  examination.  How  far  these  little-known 
bodies  have  a  practical  bearing  on  the  saponification-process  of  assay  is  uncer- 
tain, and  hence  the  results  must  be  regarded  as  tentative,  except  where  the 
method  is  applied  to  the  alkaloid  previously  obtained  in  a  crystallised  state. 

2  Alder  Wright  holds  strongly  that  all  galenical  preparations  of  aconite 
and  amorphous  alkaloids  should  be  abandoned,  and  only  well-crystallised  alka- 
loids or  their  salts  employed. 

It  is  a  grave  scandal  that,  although  the  enormous  diff'erence  in  physiological 
jiotency  between  the  crystalline  alkaloids  of  the  aconites  and  the  amorphous 
bases  associated  with  them,  or  produced  by  their  decomposition,  has  been  long 
recognised,  and  become  generally  known,  and  while  crystalline  aconitine  can 
be  readily  prepared,  that  a  preparation  should  still  be  sold  under  the  name  of 
"aconitine"  which  is  not  crystallised,  a^d   contains  a  large   proportion   of 


234  ASSAY   OF   ACONITE   ALKALOIDS. 

Alder  Wright's  saponification  experiments  were  made  on 
comparatively  large  quantities  of  the  alkaloids ;  but  to  be  of  any 
practical  value  the  method  of  assay  must  be  available  with  a 
quantity  of  aconite  bases  not  exceeding  50  milligrammes,  and 
should  even  be  applicable  with  half  that  quantity.  The  author 
has  succeeded  in  making  very  satisfactory  determinations  on  these 
small  quantities  by  the  following  method  of  operating,  which  may 
be  conveniently  applied  either  to  an  ether  or  chloroform  residue, 
or  to  the  liquid  resulting  from  the  titration  of  either  of  these  with 
standard  acid  and  methyl-orange,  as  already  described.  The 
residue  or  solution,  containing  30  to  80  milligrammes  of  alkaloid, 
is  treated  with  20  c.c.  of  rectified  spirit  (neutral  to  phenolphthalei'n) 
and  3  c.c,  of  a  solution  of  caustic  soda  in  an  equal  weight  of  water. 
The  liquid  is  then  boiled  for  an  hour  in  a  flask  under  a  reflux 
condenser,  after  which  the  alcohol  is  distilled  ofi*,  and  the  residual 
liquid  acidulated  with  hydrochloric  acid.  The  liberated  benzoic 
or  veratric  acid  is  extracted  by  agitation  with  about  15  c.c.  of 
ether,  and  the  ethereal  solution  separated  and  washed  with  succes- 
sive small  quantities  of  water,  until  the  washings  show  their 
freedom  from  mineral  acid  by  ceasing  to  redden  litmus.  The 
ethereal  liquid  is  then  separated  and  transferred  to  a  small  stoppered 
cylinder  (25  c.c.  capacity) ;  about  5  c.c.  of  water  faintly  coloured 
with  phenolphthaleiii  added  ;  and  ^  normal  baryta- water  dropped 
in  from  a  finely-divided  pipette  until  the  aqueous  layer  acquires 
a  pink  colour,  which  is  not  destroyed  by  agitation  with  the  ethereal 
stratum. 

From  the  volume  of  standard  baryta  consumed,  the  amount  of 
aromatic  acid  resulting  from  the  saponification  can  be  calculated. 
One  c.c.  of  ^  baryta  neutralises  2'44  milligrammes  of  benzoic  acid, 
or  3*64  milligrammes  of  veratric  (dimethyl-pro tocatechuic)  acid. 
Although  these  acids  have  different  combining  weights,  the  volumes 
of  alkali  neutralised  by  equivalent  weights  of  them  are,  of  course, 
identical ;  and  hence  no  grave  difference  results  in,  calculating  the 
saponifiable  alkaloid,  whether  benzoic  or  veratric  acid  has  been  pro- 
duced by  the  saponification.  Thus  : — 
1  c.c.  of  g5  baryta  represents  12*94  milligrammes  of  acoiiitine  saponified. 

i>  n  14*14  ,,  ])seudaconitine  saponified. 

n  ,,  12*44  ,,  japaconitine  sa[)Oinfitd. 

In  three  experiments,  where  a  weight  of  30  milligrammes  of  the 

practically  inactive  base.  It  is  a  question  whether  the  sale  of  such  an  impure 
preparation  as  **aconitine"  is  not  an  infringement  of  the  Sale  of  Food  and 
Drugs  Act,  notwithstanding  that  the  British  Fharviacopceia  officially  recog- 
nises the  indefinite  mixture  as  "  aconitiue,"  and  describes  it  as  "usually 
amorphous." 


ASSAY   OF   ACONITE   ALKALOIDS. 


235 


same  sample  of  crystallised  aconitine  was  saponified,  the  baryta 
solution  used  represented  3r6,  28*3  and  30-9  of  the  alkaloid.  In 
the  case  of  japaconitine  (not  quite  pure)  the  process  indicated  29"8, 
against  30  milligrammes  taken. 

If  desired,  the  titration  being  completed,  hydrochloric  acid  may 
be  added,  when  the  aromatic  acid  will  be  liberated  and  redissolved 
by  the  ether.  On  separating  this  solution  and  allowing  it  to 
evaporate  spontaneously,  the  weight  of  the  acid  may  be  ascertained 
and  its  melting-point  observed ;  or  the  ether  may  be  separated 
from  the  aqueous  liquid,  and  the  latter  acidulated,  largely  diluted 
and  distilled,  when  a  separation  of  the  benzoic  and  veratric  acids 
will  be  effected,  the  former  volatilising  with  the  steam  and  the 
latter  r^iaining  in  the  retort.  This  difference  of  behaviour 
enables  pseudaconitine  to  be  recognised  and  estimated  in  presence 
of  aconitine  and  japaconitine. 

By  the  foregoing  method  of  assaying  the  mixed  alkaloids  from 
the  tincture  of  A.  Naj^elliLS  root,^  G.  E.  Scott-Smith  obtained 
in  the  author's  laboratory  the  following  results : — 


A. 

B. 

C. 

D. 

E. 

F. 

G. 

fl. 

Weight  taken,  iu  milligrammes,    . 

55-0 

51-7 

21-9 

87-0 

21-0 

31-5 

17-2 

23-6 

Alkaloid  by  titration  (iu  temis  of  ) 
aconitine),                                    ) 

69-0 

66-7 

29-4 

... 

28-8 

... 

18-1 

24-9 

Benzoic  acid, 

5-2 

4-0 

8-4 

... 

4-8 

4  1 

=Aconitine, 

27-7 

20-4 

... 

44-5 

... 

25-7 

22-1 

Percentage  of  saponiflable  alkaloid, 

50-4 

39-5 

51-1 

... 

81-6 

56-1 

If  desired,  the  basic  product  of  the  saponification  can  be  isolated 
by  rendering  the  liquid  alkaline  with  sodium  carbonate  or  caustic 
soda,  and  agitating  with  ether  or  chloroform.  The  latter  solvent 
extracts  a  trifling  further  quantity  from  the  liquid  which  has 
already  been  treated  with  ether.  The  few  experiments  made  in 
this  direction  in  the  author's  laboratory  gave  somewhat  erratic 
results,  probably  owing  to  the  imperfect  extraction  of  the  bases  by 
immiscible  solvents,  and  the  further  action  of  the  caustic  alkali 
on  them. 

*  The  alkaloids  from  a  tincture  prepared  from  the  root  of  A.ferox  gave,  for 
767  milligrammes  taken  : — By  titration,  74*9  of  alkaloid,  calculated  as  pseud- 
aconitine ;  saponified,  14 '3  milligrammes  of  veratric  acid  by  titration,  against 
a  weight  of  IS'O  extracted  by  ether.  The  former  result  represents  55-1  of 
pseudaconitine,  leaving  21*6  of  unsaponifiable  alkaloid.  The  basic  product  of 
the  saponification  extracted  by  ether,  followed  by  chloroform,  from  the  alkaline 
residue,  amounted  to  18 '5  milligrammes,  and  neutralised  acid  equivalent  to 
51 '4  of  pseudaconine,  or  69*4  of  pseudaconitine. 


236  POISONING   BY   ACONITE. 

Toxicology  of  Aconite. 

Aconitine  is  one  of  the  most  violent  poisons  known,  and  pseud- 
aconitine  appears  to  be  fully  as  active ;  whereas  picraconitine, 
atesine,  and  some  others  of  the  natural  alkaloids  of  the  aconites 
appear  to  be  harmless  bitter  principles.  The  bases  produced  by 
the  saponification  of  the  poisonous  alkaloids  are  also  comparatively 
inert  (t^Jq  ^^  ^^^  toxicity  of  aconitine),  and  it  is  probably  to  the 
presence  of  these  and  other  relatively  inactive  bodies,  in  variable  pro- 
portion, in  the  so-called  "  aconitine  "  of  commerce  that  the  notorious 
uncertainty  in  the  activity  of  that  preparation  is  largely  due.  Some  of 
the  recorded  variations  verge  on  the  fabulous,  and  are  probably  in 
some  measure  due  to  the  experiments  being  insufficient  in  number, 
and  made  without  due  regard  to  the  difference  in  susceptibility 
to  the  poison  caused  by  age,  sex,  and  general  condition  of  the 
animals  operated  on.^  A  more  reliable  preparation  is  obtainable 
since  the  conditions  and  importance  of  obtaining  crystallised 
aconitine,  and  of  preparing  the  base  from  certain  definite  species 
of  aconite,  have  become  more  generally  recognised.^     From  certain 

^  K.  F.  Man  del  in  states  [Pharm.  Jour.,  [3],  xvi.  781),  as  the  lesult  of 
very  numerous  experiments  both  on  frogs  and  warm-blooded  animals,  that  not 
only  do  animals  of  different  species  behave  dissimilarly,  but  even  with  animals 
of  the  same  species  a  considerable  difference  can  frequently  be  observed  in 
respect  to  the  lethal  dose,  according  to  the  age  and  condition  of  nourishment. 
With  frogs,  in  particular,  considerable  differences  are  observable  ;  and  female 
frogs  are  more  susceptible  to  the  poison  than  males.  Old  animals  are  more 
susceptible  than  youDg  ones  ;  and  the  symptoms  may  vary  according  to  the 
individuality  aud  nourishment  of  the  animals  experimented  on. 

2  Some  interesting  results  of  the  action  on  sparrows  of  the  principal  makes 
of  aconitine  prepared  in  1872  have  been  described  by  H.  D  u  q  u  e  s  n  e  1  ( Year- 
Book  Pharm.,  1872,  page  241).  Administered  by  subcutaneous  injection,  in 
a  dose  of  0*0005  gramme  in  10  drops  of  slightly  acidulated  water,  crystallised 
aconitine  produced  death  in  1  minute  ;  the  alkaloid  of  the  French  Codex 
(Hottot's  preparation),  in  15  minutes  ;  Merck's  aconitine,  in  75  minutes  ; 
French  commercial  aconitine,  in  120  minutes  ;  and  Hubschmann's  napelline 
(probably  impure  aconine),  profound  sleep,  not  followed  by  death.  Hottot's 
aconitine  is  described  as  amorphous,  white,  pulverulent,  containing  20  per 
cent,  of  water,  fusible  at  80°,  and  assuming  after  loss  of  water  a  resinous  trans- 
parent appearance,  but  not  forming  crystallisable  salts. 

P.  C.  Plugge  (Archiv  der  Pharm.,  Jan.  1882)  was  led  to  investigate 
the  relative  toxicity  of  commercial  * '  aconi tines  "  in  consequence  of  a  death 
from  the  accidental  dispensing  of  Petit's  preparation,  instead  of  Friedlander's, 
which  was  intended  but  not  specified  by  the  prescriber.  Plugge  found  the 
•elative  activities  to  be,  Petit's  nitrate  of  aconitine,  170  ;  Merck's  nitrate  of 
aconitine,  20  to  30  ;  Friedlander's  aconitine,  1.  He  placed  the  various  com- 
mercial specimens  in  the  following  order,  commencing  with  the  strongest  : — 


POISONING  BY   ACONITE.  237 

observations  of  Richards  and  Rogers  {Chemist  and  Druggist, 
Feb.  7  and  14,  1891),  it  is  not  improbable  that  commercial 
crystallised  aconitine  sometimes  contains  a  large  admixture  of 
anhydro-aconitiue,  and  that  this  base  is  considerably  more  active 
than  the  parent  alkaloid  (A.  H.  Allen,  PTiarm.  Jour.,  [3],  xxii.). 
The  poisonous  effects  of  aconite  and  its  preparations  appear  to 
be  entirely  due  to  the  characteristic  alkaloids  contained  therein,^ 
and  are  generally  assumed  to  be  substantially  the  same  in  kind 
and  degree,  whether  aconitine  itself,  or  one  of  its  analogues,  pseud- 
aconitine  or^japaconitine,  be  the  base  present.^  This,  however, 
is  by  no  means  certain. 

Petit's,  Morson's,  Hottot's,  Hopkins  and  Williams',  Merck's,   Schuchardt's^ 
Friedlander's. 

E.  R.  Squibb  (Ephemeris,  i.  135)  in  1882  classified  the  four  chief  makes  of 
aconitine  as  follows  : — Duquesnel's  crystallised  aconitine,  111  ;  Merck's 
"aconitine"  from  Himalaya  root  (pseudaconitine),  83;  Merck's  ordinary 
aconitine,  8  ;  aconitine  of  unknown  make,  1  ;  powdered  aconite  root,  1. 

F.  A.  T  h  0  m  p  s  o  n,  by  employing  Squibb's  physiological  test,  classified 
various  samples  of  commercial  aconitine  as  follows  : — Gehe's  crystals,  480  ; 
Merck's,  350  ;  Duquesnel's,  300  ;  Gehe's  amorphous  alkaloid,  90  to  45. 

Buntzen  and  Mad  sen  {Pharm.  Jour.,  [3],  xvi.  366)  concluded  from 
experiments  on  frogs  that  Gehe's  amorphous  aconite  was  the  most  powerful 
of  the  specimens  examined.  Next  came  some  preparations  made  from  Vosges 
roots  ;  then  the  crystalline  preparations  of  Gehe,  Petit,  and  Merck  ;  and  after- 
wards preparations  by  Madsen  from  Swiss  roots.  Duquesnel's  aconitine  gave 
far  less  effective  results  than  other  observers  have  stated.  Great  differences 
were  observed  in  samples  of  alkaloid  from  Japanese  roots,  while  that  from 
bish  root  (pseudaconitine)  was  inferior  in  quality,  though  this  may  have  been 
due  to  the  roots  having  been  submitted  to  the  action  of  heat. 

^  H.  Duquesnel  found  that  an  alcoholic  extract  of  aconite  root,  from 
which  the  alkaloid  had  been  removed  in  the  ordinary  way  by  agitating  the 
alkaline  solution  with  ether,  when  administered  to  birds  produced  a  sound 
sleep  of  several  hours,  without  anaesthesia,  followed  by  complete  recovery. 
Larger  doses  were  fatal.  The  extract  employed  by  Duquesnel  probably  con- 
tained aconine,  which  is  imperfectly  extracted  by  ether.  Hiibschmann's 
"napelline,"  which  was  probably  impure  aconine,  produced  similar  symptoms. 
Duquesnel's  extract  would  also  contain  aconitic  acid,  which  Fleming 
found  to  have  but  little  effect  when  administered  to  rabbits  hypodermically. 
Torsellini,  however,  found  aconitic  acid  to  have  a  paralysing  effect  on 
the  heart  of  a  frog. 

^Mandelin  {Pharm.  t/bttr.,  [3],  xvi.  782)  disputes  the  statement  of 
Langgaard,  that  japaconitine  is  "  one  of  the  strongest  of  poisons,  which 
exceeds  aconitine  and  pseudaconitine  in  activity."  He  even  doubts  the 
chemical  difference  between  aconitine  and  japaconitine,  and  finds  in  both 
cases  the  lethal  dose  for  frogs  to  range  from  1*2  to  2*4  milligrammes  per 
kilogramme  of  body  weight ;  for  guinea-pigs,  0'05  milligramme;  and  for  dogs 
and  cats,  0*06  to  0*075  milligramme  per  1000  grammes. 


238  FATAL  DOSE  OF  ACONITINE. 

Poisoning  of  human  beings  by  pure  aconitine  has  been  of 
comparatively  rare  occurrence;  but  there  have  been  numerous  cases 
of  poisoning  by  the  roots,  leaves,  and  galenical  preparations  of 
aconite,  the  greater  number  being  the  result  of  accident.^  The 
root  has  been  occasionally  eaten  in  mistake  for  horse-radish,  which 
it  somewhat  resembles  (compare  page  199). 

The  medicinal  dose  of  the  B.P.  tincture  oi  aconite  is  from  5  to 
1 5  minims.  A.  Wynter  Blyth  considers  twice  the  maximum 
dose,  or  30  minims,  likely  to  be  fatal  to  an  adult,  though  the  least 
fatal  dose  is  usually  stated  at  above  twice  this  measure.  Fleming's 
tincture  of  aconite  is  from  three  to  six  times  the  strength  of  the 
B.P.  preparation.^  The  B.P.  liniment  is  eight  times  as  strong 
as  the  tincture.^  The  fatal  dose  of  aconitine  is  difficult  to  fix,  as  in 
the  few  cases  in  which  a  fatal  dose  of  the  pure  alkaloid  has  been 
administered  the  quantity  taken  has  not  been  known  ;  and  in  the 
cases  of  poisoning  by  preparations  of  aconite  there  is  the  greatest 
uncertainty  as  to  the  amount  of  alkaloid  contained  therein. 
Headland  considers  -^  grain  of  aconitine  an  ordinary  fatal  dose 
for  an  adult,  and  ^^  grain  of  the  nitrate  has  actually  caused  death. 
Death  appears  to  have  been  caused  in  one  hour  by  0*0005  gramme 
of  aconitine  (Pharm.  Jour.,  [3],  xx.  734).  Wynter  Blyth  con- 
siders "002  gramme  or  '03  grain  the  minimum  fatal  dose  for  an 
adult,  when  the  poison  is  taken  by  the  mouth  ;  but  that  if  given 
hypodermically,  0"0015  gramme  would  probably  kill,  since  the 
whole  of.  the  poison  is  then  thrown  on  the  circulation  at  one  time, 
and  there  is  no  chance  of  its  elimination  by  vomiting.  P  e  r  e  i  r  a 
relates  a  case  in  which  ^  grain  nearly  proved  fatal  to  an  elderly  lady. 
Recovery  has  occurred  after  taking  2J  grains,  but  in  this  case 
there    was    violent    vomiting    immediately,    and    most    dangerous 

^  A.  Wynter  Blyth,  in  his  work  on  Poisons,  states  that  he  had 
collected  from  European  literature,  of  the  ten  years  prior  to  1874,  eighty-seven 
cases  of  poisoning  hy  aconite  in  some  form  or  other.  In  these  were  two  cases 
of  murder,  seven  of  suicide,  and  seventy-seven  more  or  less  accidental.  Six  of 
the  cases  were  from  the  use  of  the  alkaloid  itself  ;  ten  from  the  root  ;  in  two 
cases  children  eat  the  flowers  ;  in  one  case  the  leaves  of  the  plant  were  cooked 
and  eaten  by  mistake  ;  in  seven  the  tincture  was  mistaken  for  sherry,  brandy, 
or  liqueur  ;  and  the  remainder  were  caused  by  the  tincture,  the  liniment,  or 
the  extract. 

2  Dr  Male,  of  Birmingham,  died  from  the  effects  of  80  drops  of  Fleming's 
tincture,  taken  in  ten  doses  of  8  drops  each,  in  the  course  of  four 
days. 

3  Dr  C.  Vachell,  of  CardifT,  has  published  a  case  of  fatal  poisoning  by  2  grains 
of  extract  of  aconite  taken  in  pills.  This  was  the  maximum  dose  of  extract 
according  to  the  British  Pharmacoposia  of  1867,  but  in  the  edition  of  1886 
the  dose  is  stated  at  ^  to  1  grain. 


SYMPTOMS  OF  ACONITE   POISONING.  239 

symptoms  for  thirty  hours.^  In  the  Lamson  case  {Gwjs  Hospital 
Reports,  1883,  page  307)  the  victim  probably  received  about  2 
grains.^ 

The  symptoms  of  aconite  poisoning  usually  begin  to  manifest 
themselves  a  few  minutes  after  the  poison  is  taken,  and  are,  in 
some  respects,  quite  peculiar  and  characteristic.  They  usually,  but 
not  invariably,  commence  with  a  tingling  and  numbness  of  the  lijis, 
tongue,  gums,  and  throat,  accompanied  with  a  burning  sensation 
in  the  stomach.  These  effects  are  succeeded  by  tingling  and  creep- 
ing sensations  in  various  parts  of  the  body,  pains  in  the  abdomen, 
headache,  vertigo,  and  nausea,  frequently  accompanied  by  vomiting 
and  sometimes  by  purging.  There  is,  also,  diminished  sensibility 
of  the  skin,  constriction  in  the  throat,  frothing  at  the  mouth, 
partial  or  entire  loss  of  voice,  impaired  vision,  ringing  in  the  ears, 
and  feeling  of  tightness  in  various  parts  of  the  body ;  muscular 
tremors,  cold  perspirations,  loss  of  muscular  power,  and  great 
prostration  generally.  Sometimes  there  is  alternate  contraction 
and  dilation  of  the  pupil. 

The  most  constant  symptoms  of  aconite  poisoning  are  difficulty 
in  breathing,  progressive  muscular  weakness,  a  weak  intermittent 
pulse,  and,  in  most  cases,  vomiting,  especially  when  the  poison  has 
been  taken  by  the  mouth,  instead  of  subcutaneously.  Death  usually 
occurs  from  syncope,  preceded  in  some  cases  by  delirium  and  con- 
vulsions. Convulsions  occurred  in  ten  cases  out  of  ninety-four 
collected  by  Drs  Tucker  and  Eeichert,^  and  opisthotonos  happens 

^  In  a  case  of  poisoning  by  aconite  an  emetic  should  be  at  once  given,  or 
the  stomach-pump  promptly  used.  Stimulants  may  be  given  with  advantage. 
Animal  cliarcoal,  to  be  afterwards  removed  by  the  stomach-pump,  has  been 
recommended.  Strychnine  and  digitalis  have  been  used  successfully  as 
antidotes,  and  a  solution  of  iodised  iodide  of  potassium  has  been  suggested, 

2  In  1881,  a  medical  man  named  Lamson  gave  his  brother-in-law,  P.  ]M. 
John,  a  youth  of  19,  paralysed  below  the  pelvis,  a  dose  of  Morson's  aconitine, 
contained  in  a  gelatin  capsule.  Some  twenty  or  thirty  minutes  after,  John 
was  seized  with  pain  in  the  stomach,  which  he  at  first  called  heartburn.  He 
then  vomited,  and  suffered  great  pain,  complained  of  the  skin  of  his  face 
being  drawn,  of  a  sense  of  constriction  in  the  throat,  and  of  being  unable  to 
swallow.  He  retched  violently,  and  vomited  a  small  quantity  of  dark  brown 
fluid.  Injections  of  morphine  gave  some  relief,  but  the  symptoms  returned, 
and  he  was  with  difficulty  kept  down  by  two  men.  Death  occurred  four  hours 
after  administration  of  the  poison,  and  the  victim  was  conscious  almost  to  the 
last. 

*  These  symptoms  probably  depend  largely  on  the  dose  taken.  "With  large 
doses,  the  heart's  action  is  arrested  before  the  poison  has  had  time  to  materially 
affect  the  excitability  of  the  motor  nerves,  and  the  heart  once  stopped,  further 
absorption  is  diminislied  or  arrested. 


240  DETECTION   OF  ACONITE   POISONING. 

occasionally.  Death  from  aconite  poisoning  commonly  ensues  in 
from  two  to  six  hours,  though  there  is  considerable  variation  in 
this  respect.^ 

The  post-mortem  appearances  from  aconite  poisoning  are  by  no 
means  characteristic.  They  are  congestion  of  the  lungs  and  liver, 
with  an  injected  condition  of  the  brain  and  its  membranes.  There 
is  more  or  less  redness  of  the  stomach  and  intestines,  which  are 
frequently  found  empty.  Great  redness  of  the  stomach  and 
intestines  is  sometimes  the  only  abnormal  appearance  after  aconite 
poisoning,  and  this  does  not  occur  when  the  poison  has  been  given 
hypodermically.  The  right  side  of  the  heart  usually  contains  more 
or  less  blood,  and  the  blood  throughout  the  body  is  generally  fluid 
and  dark  in  colour.- 

TOXICOLOGICAL    DETECTION    OF    AcONITE. 

In  any  case  of  suspected  poisoning  by  aconite  or  its  preparations, 
the  symptoms  presented  before  and  after  death  are  of  the  utmost 
importance.^  The  poison  is  so  violent,  so  readily  decomposed,  and 
so  wanting  in  delicate  and  characteristic  chemical  reactions,  that 
there  is  but  little  hope  of  detecting  it  in  the  body  by  chemical 
analysis.  With  care,  however,  this  may  sometimes  be  effected,  and 
if  the  chemical  reactions  be  distinctly  confirmed  by  a  physiological 
test,  the  presence  of  the  poison  may  be  considered  definitely  proved. 
The  aconite  alkaloids  have  been  recovered  from  the  urine,  the 
blood,  and  the  liver,  and  have  been  detected  in  the  stomach  several 
months  after  death ;  but  the  poison  has  been  destroyed  in  cases 
where  the  viscera  have  become  and  remained  alkaline  for  some  time 
from  putrefactive  decomposition. 

In  cases  of  supposed  poisoning  by  aconite,  the  stomach  and 
intestines  should  be  carefully  examined  for  portions  of  the  leaves 
or  other  parts  of  the  plant ;  which,  if  found,  may  be  identified  by 

^  In  five  cases  of  aconite  poisoning  recorded  by  J.  W.  Mallet,  death 
ensued  respectively  in  8,  10,  15,  75,  and  135  minutes,  while  in  a  sixth  case  it 
did  not  occur  till  four  days  after  the  poison  was  taken. 

2  In  the  Lamson  case,  sixty-four  hours  after  death,  there  was  great  redness 
and  inflammation  of  the  cardiac  end  of  the  stomach,  which  had  a  bUstered 
appearance,  the  mucous  membrane  showing  in  "places  small,  slightly  raised, 
yellowish  grey  patches.  The  duodenum  was  greatly  congested,  and  there  were 
congested  patches  in  other  parts  of  the  small  intestine.  The  brain  and  its 
membranes  were  slightly  congested,  and  the  lungs  much  so,  especially  towards 
the  posterior  parts.  The  heart  was  very  flaccid,  nearly  empty,  and  stained 
with  blood-pigment.  Tlie  pupils  were  dilated,  and  the  lips  and  tongue  pale. 
The  bladder  contained  three  or  four  ounces  of  urine. 

^  It  is  for  this  reason  that  the  symptoms  of  aconite  poisoning  are  described 
in  the  text  at  greater  lengtli  than  would  appear  necessary  in  a  work  treating 
of  the  chemist's  duties  ratiier  than  those  of  the  medical  practitioner. 


DETECTION   OF  ACONITE  POISONING.  241 

comparison  of  their  botanical  characters  with  those  of  real  aconite. 
The  fragments  may  be  washed  with  a  little  distilled  water,  and 
masticated  with  the  front  teeth,  when  the  persistent  tingling  and 
numbness  so  characteristic  of  aconite  will  be  distinctly  recognisable. 

For  the  isolation  of  aconite  bases  in  cases  of  poisoning,  the 
suspected  matters  should  be  finely  divided  and  treated  at  the 
ordinary  temperature  with  strong  alcohol,  which  should  be  slightly 
acidulated  with  tartaric  acid,  unless  already  distinctly  acid.  The 
liquid  is  strained  and  evaporated  to  a  low  bulk  at  a  temperature 
not  exceeding  40°  C.  The  residual  liquid  is  filtered  cold,  acidulated 
with  tartaric  acid,  if  requisite,  shaken  with  ether,  separated,  and 
rendered  alkaline  with  sodium  carbonate.  The  alkaloids  are  then 
extracted  by  agitation  with  ether  or  ether-chloroform,  the  solution 
washed  by  agitation  with  water,  and  evaporated  at  a  gentle  heat. 

The  alkaloidal  residue  having  been  obtained,  it  should  be  dis- 
solved in  a  few  drops  of  water  acidulated  with  acetic  acid,  and  a 
drop  of  the  solution  placed  on  the  tip  of  the  tongue  or  inside  the 
lower  lip.  E.  R.  Squibb  recommends  that  the  quantity  to  be 
tasted  should  be  dissolved  in  about  60  drops  of  water,  which  is 
then  held  in  the  front  part  of  the  mouth  (previously  rinsed)  for 
one  minute,  and  then  discharged.  Another  good  plan  is  to  drop 
the  solution  on  a  fragment  of  porous  biscuit,  which  is  then  chewed 
with  the  front  teeth.  If  any  aconitine  or  other  poisonous  aconite 
base  be  present  it  will  produce,  in  a  period  of  time  not  exceeding 
fifteen  minutes,  a  marked  tingling  sensation  of  the  tongue  and  lips 
(somewhat  similar  to  the  effect  produced  by  scalding  the  tongue 
with  hot  tea) ;  and,  if  the  quantity  be  sufficient  and  the  liquid  has 
reached  the  tonsils  a  distinct  sensation  of  sore  throat  will  be 
observed.  These  effects  last  for  a  considerable  time,  and  are  pro- 
duced in  a  most  marked  and  unmistakable  manner  by  a  single 
drop  of  the  B.P.  tincture  of  aconite,  corresponding  to  \  grain  of 
the  root,  and  probably  not  more  than  j^qq  grain  of  total  alkaloids. 
The  effect  is  so  characteristic  and  delicate  that  it  constitutes  by  far 
the  best  test  for  the  presence  of  the  poison.  If  not  produced  it  is 
practically  useless  to  apply  other  tests,  as,  in  the  absence  of  the 
physiological  reaction  they  would  at  least  be  inconclusive ;  but, 
having  obtained  the  characteristic  tingling  sensation,  the  chemical 
tests  often  afford  useful  confirmation,  and  enable  the  analyst  to 
form  an  opinion  as  to  whether  pure  aconitine  or  a  galenical 
preparation  of  the  aconite  plant  was  taken.^ 

^  An  interesting  case  of  this  kind  has  occurred  in  the  author's  personal 

experience.     A  man  of  suicidal  tendencies  was  suddenly  taken  violently  ill  at 

a  country  inn.     He  suffered  from  difficulty  of  respiration  and  inability  to  use 

his  limbs,  especially  on  one  side,  had  violent  convulsions,  and  died  before 

VOL.  III.  PART  II.  Q 


242  DETECTION   OF  ACONITE   POISONING. 

The  chemical  tests  should  be  applied  to  single  drops  of  the 
acidulated  solution  placed  on  microscope-slides ;  or,  in  the  case  of 
the  colour-tests,  to  the  residues  left  on  evaporating  a  few  drops  at 
a  gentle  heat  on  the  inside  of  a  porcelain  crucible  cover  (compare 
page  145).     The  reactions  which  may  prove  of  service  are  : — 

1.  The  formation  of  a  crystalline  nitrate  on  adding  a  small  drop 
of  nitric  acid  at  the  end  of  a  glass  rod  (page  210). 

2.  The  formation  of  a  crystalline  aurochloride  on  adding  a  drop 
of  auric  chloride  (page  211). 

3.  The  formation  of  crystals  of  aconitine  hydriodide  on  adding 
a  minute  fragment  of  potassium  iodide,  and  allowing  the  solution 
to  evaporate  (page  212). 

4.  On  adding  cold  concentrated  sulphuric  acid  to  the  aconite 
residue  no  reaction  is  produced  immediately,  but  very  gradually,  or 
more  rapidly  on  cautiously  warming,  a  deep  brown  coloration  is 
produced,  passing  through  various  shades  of  reddish  brown  to 
violet.     The  reaction  is  not  produced  by  pure  aconitine. 

5.  In  presence  of  certain  impurities,  which  adhere  tenaciously, 
aconite  bases  develop  a  well-marked  cherry-red  coloration,  changing 
to  crimson,  when  treated  with  sugar  and  sulphuric  acid  in  the 
manner  described  under  morphine.  The  mixture  of  bases  extracted 
from  aconite  root  in  the  ordinary  process  of  assay  gives  this  reac- 
tion very  distinctly. 

6.  Impure  residues  of  aconite  bases,  when  treated  with  syrupy 
phosphoric  acid,  give  a  violet  coloration  when  the  mixture  is 
heated  for  some  time  on  the  water-bath,  so  as  gradually  to  concen- 
trate the  acid. 

7.  Aconitine  yields  with  phosphomolybdic  acid  (Sonnenschein's 
reagent)  a  yellow  precipitate,  which,  in  the  presence  of  impurities, 
dissolves  in  ammonia  with  blue  colour. 

When  the  tongue-test  renders  the  presence  of  an  aconite  base 
probable,  it  is  very  desirable  to  make  a  further  physiological 
experiment  on  a  small  animal.  For  this  purpose  a  quantity  of 
residue  or  solution  at  least  as  great  as  that  used  for  the  tongue- 
test,  and  preferably  several  times  as  large,  is  made  into  one  or 
more  small  pills  with  oatmeal,  and  given  to  a  mouse  or  small  bird 
by  the  mouth.  It  is  distinctly  preferable  to  operate  in  this  manner 
rather  than  by  hypodermic  injection,  in  the  case  of  such  small 

medical  assistance  could  be  obtained.  On  analysis,  an  alkaloidal  substance 
was  isolated  from  the  stomach,  which  gave  exactly  similar  colour-reactions  to 
the  alkaloid  extracted  by  the  same  means  from  the  B.P.  tincture  of  aconite. 
It  produced  a  distinct  tingling  sensation  on  the  tongue  and  lips,  and  charac- 
teristic symptoms  in  a  mouse  which  had  eaten  a  portion  of  the  extract  made 
into  a  pill  with  oatmeal. 


MANDRAGOKINE.  243 

and  sensitive  animals  as  those  which  must  almost  necessarily  be 
employed.  If  two  healthy  (white)  mice  be  chosen,  and  one  fed 
with  ordinary  oatmeal  made  into  pills,  and  the  other  with  oatmeal 
pills  made  with  the  alkaloidal  extract,  the  symptoms  may  be  readily 
compared,  and  several  objections  obviated.  According  to  W  y  n  t  e  r 
B 1  y  t  h,  a  quantity  of  aconite  extract  sufficient  to  cause  distinct 
numbness  of  the  lips  will  kill  a  mouse  or  small  bird  if  administered 
in  this  manner.^  J.  H.  Munro  (Chem.  News,  xlv.  110)  has 
described  an  experiment  in  which  he  poisoned  a  sparrow  with  O'l 
grain  of  aconite  root.  Death  ensued  within  an  hour.  The  con- 
tents of  the  gizzard  were  mixed  with  the  little  which  remained  in 
the  crop,  and  the  alkaloid  isolated.  The  extract  did  not  respond 
to  the  taste  or  any  chemical  test ;  but  the  solution,  when  soaked  up 
in  bread-crumbs,  and  given  to  a  torn -tit,  killed  the  bird  in  two  or 
three  hours. 


ATROPINE  AND  ITS  ALLIES.    TROPElNES.^ 

A  remarkable  series  of  natural  alkaloids  exist  in  the  plants  of  the 
family  Solanacece,  and  have  been  named,  according  to  the  plants  in 
which  they  have  been  found,  hyoscyamine  and  hyoscine, 
from  Hyoscyamus  niger  (henbane)  and  H.  albus  ;  atropine  and 
belladonnine,  from  Atropa  belladonna  (deadly  nightshade) ; 
daturine,  from  Datura  stramonium  (thorn-apple) ;  duboisine, 
from  Duboisia  myopordides ;  scopolamine,  from  Scopolia  japo- 
nica;  mandragorine,^  from  Mandragora  vernalis,  &c.    All  these 

^T.  Stevenson  found  -g-gV?  grain  of  Morson's  crystallised  aconitine, 
hypodermically  injected,  fatal  to  a  mouse  in  eighteen  minutes.  T.  G. 
Wormley  found  Duquesnel's  aconitine  equally  potent,  -^-^  grain  proving 
fatal  to  a  mouse,  after  violent  retching  and  convulsions,  in  thirty-two 
minutes. 

^  The  author  is  indebted  to  Mr  A.  W.  Gerrard  and  Mr  R.  Wright 
for  perusal  and  correction  of  this  section. 

*  Mandragorine,  the  alkaloid  of  the  root  of  Mandragora  vernalis,  has 
been  investigated  by  F.  B.  Ahrens  (Annalen,  ccli.  312;  Ber.,  xxii.  2159  ; 
Jour.  Sac.  Chem.  Ind.,  viii.  814,  915).  The  analysis  best  accords  with  the 
formula  C17H27NO3,  but  does  not  exclude  the  possibility  of  C17H.3NO3 
representing  the  true  composition.  As  extracted  by  ammonia  and  ether- 
chloroform,  the  base  is  obtained  as  a  very  deliquescent,  colourless,  vitreous 
mass,  melting  at  77°-79°.  The  sulphate  forms  small,  white  deliquescent 
plates,  and  the  hydrochloride  deliquescent  needles.  The  aurochloride  forms 
golden-yellow  plates  or  needles  melting  at  153°-155°.  BHaPtClg  crystallises 
from  hot  water  in  yellow  tables,  melting  with  decomposition  at  193°-194°. 
The  mercuro-chloride  crystallises  from  water  or  alcohol  in  slightly  soluble 
needles  or  tables,  which  melt  at  160°-16l°.     Mandragorine  is  precipitated  by 


244 


NATURAL  TROPEINES. 


bases  are  distinguished  by  a  remarkable  power  of  dilating  the  pupil, 
and  hence  are  often  termed  the  "mydriatic  alkaloid s," 
though  the  effect  of  pupil-dilation,  or  mydriasis^  is  not  confined  to 
the  alkaloids  of  the  Solaiiaceoe. 

More  recent  investigations  have  reduced  the  number  of  the 
bases  supposed  to  exist  in  the  Solanacece.  Thus,  it  appears  that  the 
bases  isolated  from  A.  belladonna  and  D.  stramonium  were  simply 
a  mixture  of  atropine  and  hyoscyamine  in  varying  proportions,  and 
that  hyoscyamine  is  converted  into  atropine  with  such  facility  in 
presence  of  a  trace  of  alkali,  that  it  is  not  improbable  that  atropine 
does  not  always  pre-exist  in  belladonna  (see  page  250).  Similarly, 
the  alkaloid  described  as  duboisine  is  apparently  identical  with 
hyoscyamine,  or  with  a  mixture  of  that  base  and  hyoscine. 


Constitution  of  Atropine  and  its  Allies. 

The  three  best-known  of  the  natural  tropeines,  viz.,  atropine, 
hyoscyamine  and  hyoscine,  are  all  isomeric,  being  expressed  by 
the  formula  C^p^HggNOg.  The  associated  bases  belladonuine  and 
atropamine  differ  from  these  by  the  elements  of  water,  and  are 
probably  anhydro-bases  (page  251).  All  these  alkaloids  are  readily 
saponifiable,  and  traces  of  the  products  of  their  hydrolysis  are 
therefore  liable  to  pre-exist  with  them  in  the  plant,  or  to  be  pro- 
duced during  the  process  of  isolation.  The  following  table  exhibits 
the  leading  properties  of  the  natural  tropeines  :  ^ — 


Base. 

Formula. 

Melting- 

Point, 

'C. 

Specific 
Rotation. 

Form. 

Products  of  Saponification 
by  Baryta. 

Acid. 

Base. 

Atropine, 

Hyoscyamine, 

Hyoscine, 

Belladonuine, 

Atropamine,  . 

Scopolamine, . 

Benzoyl-pseudo- 
tropine, 

C17H23NO3 
C17H23NO3 
C17H23NO3 
C17H21NO2 
C17H21NO2 

Ci7H2iN04 

C17H19N02 

114-5 
108-5 

Below  60 
49 

-f0°to-r-9 

-21" 

... 

+0' 

Inactive. 

Needles. 

Needles  or 

prisms. 
Colourless 

Amorphous. 

Varnish.      | 

Radiating 
crystals. 

Tropic  acid. 

Tropic  acid. 

Tropic  acid. 

Isomers  of 
tropic  and 
atropic  acids. 

Atropic  acid. 

Benzoic  acid. 

Tropine. 

Tropin  e. 

Pseudotropine. 

Pseudotropine. 

Pseudotropme. 

Base     melting 

at  110°. 
Pseudotropine. 

picric  acid,  phosphotungstic  acid,  and  iodised  potassium  iodide,  which  last 
yields  an  oily  period  ide.  Mandragorine  and  its  salts  produce  mydriasis, 
whether  introduced  into  the  system  or  directly  applied  to  the  eye. 

^  The  pre-existence  of  atropamine  and  belladonnine  in  the  plants  is  not 
absolutely  estabhshed. 


HYDROLYSIS   OF  TROPEINES.  246 

The  natural  tropeines  are  all  easily  saponified  by  treatment  with 
acids  or  alkalies.  By  the  latter  (especially  baryta)  the  hydrolysis 
results  in  the  formation  of  tropic  acid,  or  an  isomer  thereof,^ 
and  tropine  or  pseudotropine,  in  accordance  with  the 
equation : — 

C„H23N03+H,0  =  C,Hj,03+C8Hi5NO. 

Tropeme.  Acid.  Base. 

When  the  hydrolysis  is  efi'ected  by  an  acid,  especially  con- 
centrated hydrochloric  acid,  the  tropic  acid  loses  the  elements  of 
water,  and  atropic  acid,  CgHgOg,  results,  and  at  a  high  tem- 
perature this  is  more  or  less  changed  into  its  polymers  a-  and 
j8-isatropic  acid,  C^gH^gOg.  Such  products  also  result  from 
the  saponification  of  the  anhydro-bases  belladonnine  and  atropamine 
by  baryta. 

The  preferable  method  of  effecting  the  saponification  of  the 
tropeines  is  to  heat  the  alkaloid  with  saturated  baryta-water  to 
60°  or  80°  C.  for  a  few  hours.  Carbon  dioxide  is  next  passed 
tlirough  the  liquid  till  a  drop  ceases  to  give  a  pink  coloration  with 
phenolphthalein.  The  liquid  is  then  filtered,  and  the  filtrate 
acidulated  with  hydrochloric  acid  and  twice  shaken  with  ether. 
The  ether  is  separated,  and  on  evaporation  yields  the  acid 
product  of  the  hydrolysis ;  on  treating  the  aqueous  layer  with 
caustic  alkali  in  excess  and  agitating  with  ether  the  basic 
product  is  extracted,  and  may  be  recovered  by  separating  and 
evaporating  the  ether. 

Tropic  Acid,  C6H5.CH(CH2.0H)C0.0H,  has  the  constitution  of 
a-phenyl-/3-hydroxy propionic  acid.  It  crystallises 
from  hot  water  in  needles  or  slender  prisms,  and  on  the  spontane- 
ous evaporation  of  its  aqueous  solution  in  tablets  which  melt  at 
117°- 118°  C.  Tropic  acid  is  not  volatile  without  decomposition. 
It  has  a  slightly  sour  taste,  dissolves  in  40  parts  of  cold  water, 
and  is  soluble  in  alcohol  and  ether.  When  heated  with  a  dilute 
solution  of  potassium  permanganate,  tropic  acid  gives  an  odour  of 
bitter-almond  oil,  and  on  further  treatment,  benzoic  acid  is  pro- 
duced. 

Tropic  acid  has  been  prepared  synthetically  (Ber.,  xiii. 
2041). 

Atropic  Acid,  CgH5.C(CH2).CO.OH,  has  the  constitution  of 
o-phenylacrylic  acid.  It  is  isomeric  with  cinnamic  acid 
(Part  I.  page  30),  from  which  it  differs  by  its  solubility  in  water 

^  Except  in  the  case  of  benzoyl-pseudotropine,    which  yields   benzoic 
acid  on  hydrolysis. 


246  TROPIC  ACID.      TROPINE. 

(1  in  692  at  19°),  its  lower  melting-point,  and  in  not  being  pre- 
cipitated by  manganous  salts  from  its  neutral  solutions.  Atropic 
acid  has  been  prepared  synthetically,  and  may  also  be  obtained 
by  heating  tropic  acid  with  hydrochloric  acid,  or  by  the  direct 
action  of  fuming  hydrochloric  acid  at  120°,  or  boiling  concentrated 
baryta-water,  on  atropine.  It  crystallises  from  hot  water  in  needles, 
and  from  alcohol  in  tablets  or  monoclinic  prisms,  which  melt  at 
106°— 107°,  are  volatile  with  steam,  and  boil  with  decomposition 
at  about  267°.  Atropic  acid  is  very  soluble  in  carbon  disulphide. 
It  is  oxidised  to  benzoic  acid  by  chromic  acid  mixture,  and 
yields  formic  and  phenylacetic  acids  when  fused  with 
caustic  potash.  Sodium -amalgam  reduces  it  to  a-phenyl- 
propionic  acid.  Bromine-water  converts  it  into  bromo- 
phenylpropionic  acid. 

IsATROPic  Acid,  Ci8^i6^4'  ^^  polymeric  with  atropic  acid, 
CgHgOg,  and  is  always  formed  together  with  that  acid  and  tropic 
acid  when  atropine  is  heated  with  hydrochloric  acid.  Isatropic 
acid  is  always  formed  in  small  quantity  when  atropic  acid  is 
recrystallised  from  hot  water,  and  more  largely  if  the  solution  be 
boiled  for  some  time. 

Several  isomeric  modifications  of  isatropic  acid  exist;  the 
a-isairopic  acid  is  almost  exclusively  formed  when  atropic  acid  is 
heated  for  many  hours  to  140°— 160°  in  a  closed  flask.  It  forms 
small  warty  crystals  which  melt  at  237°,  are  very  slightly  soluble  in 
water,  and  nearly  insoluble  in  ether.  It  is  not  affected  by  sodium- 
amalgam  or  cold  bromine-water.  /B-isatropic  acid  is  formed 
together  with  much  of  the  a-modification  when  the  aqueous 
solution  of  atropic  acid  is  boiled,  and  crystallises  on  cooling  in 
small  quadratic  tablets,  which  melt  at  206°,  and  are  converted  at 
220°— 225°  into  the  a-acid.  y-  and  (5-isatropic  acids  were  obtained 
by  Liebermann  by  the  saponification  of  truxilline  (cocamine), 
a  base  contained  in  some  varieties  of  coca  leaves.  From  their 
source  he  subsequently  named  them  a-  and  ^8-truxillic  acids  (com- 
pare page  286). 

Tropins,  Cfi^{C2S.4^.0B.)lii.CIL^  has  the  constitution  of  a 
tetrahydropyridine,  C5H9N,  in  which  two  of  the  hydrogen 
atoms  are  replaced  respectively  by  methyl  and  hydroxy  ethyl.  It 
is  the  basic  product  of  the  saponification  of  both  atropine  and 
hyoscyamine  (see  page  244).  -  Tropine  crystallises  from  absolute 
ether  in  rhombic  tablets,  melting  at  61°-62°  and  boiling  at  229°. 
It  is  hygroscopic,  and  very  easily  soluble  in  water  and  alcohol, 
remaining  as  an  oil  on  evaporating  these  solutions.  Tropine  is  a 
strong  tertiary  base  and  forms  salts  which  crystallise  well. 
BgHgPtClg  forms  large,  orange-red  monoclinic  prisms,  easily  soluble 


PSEUDOTROPINE.  247 

in  warm  water,  insoluble  in  alcohol,  and  melting  with  decomposition 
at  198°-200°.  BHAuCl^  forms  large  yellow  plates,  melting  with 
decomposition  at  210°-212°.  The  picrate  is  a  yellow  precipitate, 
crystallising  from  hot  water  in  yellow  needles.  On  ignition  with 
soda-lime  or  caustic  baryta,  tropine  yields  methylamine,  water 
and  t  r  o  p  i  1  i  d  e  n  e :— CgHigNO  =  CHgNHg  +  H2O  +  C^Hg.  When 
heated  with  fuming  hydrochloric  acid  to  180°,  or  with  glacial 
acetic  and  strong  sulphuric  acid,  it  loses  the  elements  of  water  and 
is  converted  into  t  r  0  p  i  d  i  n  e,  (^^^{G^^^.CE.^,  a  liquid  base 
boiling  at  1 62°,  smelling  like  conine,  and  interesting  from  its  relation 
to  anhydro-ecgonine  (compare  page  270). 

PsEUDOTROPiNE,  CgH^gNO,  is  isomcric  with  tropine,  and  results 
from  the  hydrolysis  of  hyoscine,  belladonnine  and  atropamine. 
It  forms  rhombohedral  crystals,  melting  at  106°  and  boiling  at 
241°  to  243°.  It  is  less  hygroscopic  than  tropine,  but  very  soluble 
in  water  and  chloroform,  and  somewhat  sjjaringly  in  ether. 
BgHaPtClg  forms  small  orange-red  rhombic  prisms,  easily  soluble 
in  water.     BHAuCl^  forms  small  crystals  melting  at  198°.^ 

By  treating  pseudotropine  with  strong  hydrochloric  or  sulphuric 
acid,  abase  isomeric  with  tropidine  has  been  obtained. 

Atropine.     Daturine.     Tropyl-tropine. 
C17H23NO3;  or  C5H7(C2H40.CO.CHC6H5.CH2.0H)N.CH8. 

Atropine  is  the  characteristic  alkaloid  of  Atropa  belladonna  or 
deadly  nightshade,  though  it  appears  sometimes  to  be 
wholly  or  in  great  part  replaced  by  its  isomer  hyoscyamine.^     It 

^  The  melting-point  of  the  aurochloride  is  almost  the  only  marked  distinc- 
tion between  the  pseudotropine  produced  by  the  hydrolysis  of  hyoscine  and 
the  (possibly  identical)  pseudotropine  described  by  Liebermann  {Ber., 
xxiv.  2336),  as  resulting  from  the  saponification  of  the  henzoyl-pseudotropine 
discovered  by  Gieselin  coca  leaves  from  Java.  After  boiling  this  base  with 
hydrochloric  acid  for  some  hours  the  benzoic  acid  formed  was  extracted  with 
ether,  and  the  acid  liquid  evaporated  to  dryness.  The  hydrochloride  was 
decomposed  by  oxide  of  silver;  or  excess  of  strong  caustic  soda  solution  added, 
and  the  base  extracted  with  ether.  Pseudotropine  thus  obtained  has  a 
strong  alkaline  reaction,  crystallises  in  beautiful  needles,  melts  at  106°-107'', 
boils  at  240°-241°,  and  is  easily  soluble  in  water,  alcohol,  and  benzene;  and  is 
precipitated  by  petroleum  spirit  from  the  last  solution.  BHCl  forms  hygro- 
scopic needles,  the  solution  of  which  is  precipitated  white  by  mercuric  chloride. 
BH^PtClg  does  not  crystallise  till  the  solution  is  evaporated  nearly  to  dryness, 
but  is  then  difficult  to  redissoTve  in  water,  and  is  precipitated  on  adding  alcohol. 
BHAUCI4  forms  beautiful  yellow  needles,  melting  at  225°,  and  easily  soluble 
in  hot  water  and  alcohol.     The  picrate  forms  easily  soluble,  yellow  needles. 

2  See  an  interesting  paper  by  S  c  h  ii  t  t  e,  Pharm.  Jour. ,  [3],  xxii.  429  (from 
Archiv,  October  30th.  1891,  page  492). 


248  ATROPINE. 

also  occurs  in  the  seeds  of  Datura  stramonium  or  thorn-apple, 
whence  its  name  daturine.-^  Atropine  has  been  prepared  syntheti- 
cally by  heating  together  at  100°,  with  dilute  hydrochloric  acid,  the 
tropic  acid  and  tropine  resulting  from  the  hydrolysis  of  hyoscyamine 
(page  244).  The  direct  conversion  of  hyoscyamine  into  atropine 
has  also  been  efifected  (page  250),  though  the  reverse  change  does 
not  appear  to  have  been  realised. 

Pure  atropine  forms  tufts  or  groups  of  colourless  or  white 
lustrous  needles,  or  acicular  prisms.  In  commerce  it  often  occurs 
as  a  crystalline  or  nearly  amorphous  yellowish  powder.  By  pro- 
longed exposure  to  air  it  gradually  acquires  a  yellowish  or  darker 
tint.  It  melts  when  pure  at  114°  C.  according  to  Ladenburg, 
or  at  115°— 115°'5  according  to  Schmidt;  but  the  commercial 
alkaloid  often  begins  to  melt  at  about  104°,  and  is  entirely  melted 
at  1 13°.^  At  a  higher  temperature  atropine  shows  signs  of  volatility, 
and,  according  to  Dragendorff,  volatilises  slightly  with  steam, 
and  even  with  alcohol-vapour.  When  dry,  however,  atropine  does 
not  lose  weight  by  exposure  to  100°  C. 

Atropine  is  odourless,  but  has  a  disagreeable  bitter  and  acrid 
taste.  It  is  a  powerful  poison,  producing  delirium  and  convulsions 
(page  261).  From  0'05  to  0*2  gramme  is  commonly  fatal,  and 
0*001  gramme  the  maximum  medical  dose  for  an  adult.  Much 
smaller  amounts  than  this  produce  marked  mydriasis  or  dilation 
of  the  pupil  when  applied  to  the  eye  (page  255). 

Atropine  is  soluble  in  600  parts  of  cold  or  35  of  boiling  water; 
or,  according  to  other  authority,  in  200  parts  of  cold  and  54  of 
^  For  the  preparation  of  atropine  from  belladonna,  tlie  dried  leaves  should 
be  macerated  for  several  days  in  cold  water,  the  liquid  concentrated  by  evapora- 
tion, treated  with  sodium  carbonate,  and  agitated  with  benzene.  The  benzene 
solution  is  separated  and  agitated  with  dilute  sulphuric  acid,  and  the  acid 
liquid  again  rendered  alkaline  with  sodium  carbonate,  and  the  liberated  alkaloid 
extracted  with  chloroform,  the  solution  in  which,  when  mixed  with  petro- 
leum spirit  and  allowed  to  evaporate  spontaneously,  deposits  the  atropine  first, 
while  the  associated  alkaloids  remain  in  the  mother-liquid.  It  is,  perhaps, 
more  easy  to  prepare  atropine  from  belladonna  root.  Chloroform  is  the  best 
solvent  for  the  extraction  of  atropine  from  an  alkaline  liquid,  but  ether  is  pre- 
ferable for  its  subsequent  purification  and  crystallisation  (A.  W.  G  e  r  r  a  r  d). 

^  In  a  private  communication  to  the  author,  A.  W.  Gerrard  states  that 
pure  atropine  melts  at  114°-115°.  If  some  of  the  same  sample  be  placed  in 
water  it  melts  at  83°-84°.  This  result  is  evidently  due  to  hydration,  for  the 
substance,  after  contact  Avith  water,  melts  at  the  same  temperature  in  a  capil- 
lary tube  ;  but  by  exposure  over  strong  sulphuric  acid  the  alkaloid  loses  its 
water,  and  then  again  melts  at  114°-115°.  Operating  on  the  same  specimen 
of  atropine  as  Gerrard,  the  author  observed  a  melting-point  of  114°*5,  when  a 
fragment  of  the  substance  was  heated  on  the  surface  of  mercury  contained  in  a 
test-tube  immersed  in  a  bath  of  paraffin. 


SALTS   OF  ATROPINE.  249 

boiling  water.  The  aqueous  solution  undergoes  rapid  change  in 
contact  with  air,  becoming  yellow  and  acquiring  a  disagreeable 
smell,  but  without  losing  its  toxic  character.  Atropine  dissolves 
in  glycerin,  and  is  readily  soluble  in  alcohol,  ether  (60  parts), 
chloroform  (3  parts),  amylic  alcohol  and  benzene  (42  parts),  but  is 
only  slightly  soluble  in  petroleum  spirit  or  carbon  disulphide.  The 
solutions  are  optically  inactive,  or  very  feebly  Isevo-rotatory. 

The  aqueous  solution  of  atropine  exhibits  a  distinct  alkaline 
reaction  to  litmus,  and  also  reddens  phenolphthalein,  the  latter 
character  distinguishing  atropine  and  its  isomers  from  almost  all 
other  known  alkaloids  (page  256). 

Other  reactions  of  atropine  are  described  on  page  254,  et  seq.  By 
treatment  with  alkalies  or  mineral  acids,  atropine  readily  under- 
goes saponification  (page  245),  but  is  not  altered  by  boiling  with 
strong  tartaric  acid  (compare  page  206).  By  strong  nitric  acid  it 
is  converted  into  a  n  h  y  d  r  o-a  t  r  o  p  i  n  e  (page  251). 

Atropine  Sulphate,  BgllgSO^,  prepared  by  neutralising  atropine 
with  dilute  sulphuric  acid  and  evaporating  the  solution  to  dryness 
at  100°,  is  colourless  and  odourless,  neutral,  easily  soluble  in  water 
and  alcohol,  but  less  readily  in  ether.  The  commercial  salt  is 
usually  faintly  alkaline,  and  keeps  better  when  so  made.  The 
aqueous  solution  should  be  neutral  or  faintly  alkaline  to  litmus. 

According  to  E.  Schmidt,  the  more  hyoscyaniine  a  sample  of 
commercial  atropine  sulphate  contains  the  finer  is  its  crystalline 
appearance,  the  pure  salt  occurring  as  granular  white  masses.  The 
absence  of  hyoscyamine  is  shown  by  the  solution  of  the  sample 
being  optically  inactive. 

Atropine  borate  and  valerate  are  employed  in  ophthalmic  surgery. 

Commercial  Atropine  and  its  Salts  should  be  free  from  yellow 
colour,  and  should  not  become  coloured  on  treatment  with  strong 
sulphuric  acid  or  excess  of  ammonia.  The  substance  should  leave 
no  appreciable  residue  on  gentle  ignition.  A  drop  of  a  solution  in 
1000  parts  of  water  should  have  an  acrid  and  bitter  taste,  and 
yield  a  non-lustrous  golden-yellow  precipitate  with  a  drop  of  auric 
chloride,  which  melts  under  boiling  water.  One  drop  of  a  solution 
of  atropine  in  45,000  parts  of  water  (or  less  than  2  grains  per 
gallon),  when  placed  in  the  human  eye,  should  cause  dilation  of 
the  pupil  in  from  forty  to  sixty  minutes. 

Hyoscyamine.     Daturine.     Duboisine.     C17H23NO3. 

This  base  occurs  in  belladonna,  stramonium,  and  other  solan- 
aceous  plants  in  association  with  atropine,^  with  which  alkaloid  it 

^  Hyoscyamine  occurs  in  the  seeds,  leaves,  and  roots  of  henbane  and  other 
«pecies  of  Hyoscyamus,  in  association  with  hyoscine.     It  accompanies  atropine 


250  HYOSCYAMINE — HYOSCINE. 

is  isomeric;  indeed  Ladenburg  {Ber.,  xxi.  3065)  holds  that 
atropine  is  an  optically  inactive  base,  standing  to  the  active  hyos- 
cyamine  in  the  same  relation  as  racemic  acid  stands  to  Isevo-tartaric 
acid.  At  any  rate,  by  keeping  hyoscyamine  at  a  temperature 
slightly  above  its  melting-point  the  optical  activity  gradually  falls, 
and  the  product  is  found  to  consist  of  atropine.^  Conversion  of 
hyoscyamine  into  atropine  also  occurs  when  its  cold  alcoholic  solu- 
tion is  allowed  to  stand  after  a  slight  addition  of  caustic  potash  or 
soda,  or  even  of  ammonia;  but  as  the  specific  rotation  of  the 
product  never  falls  below  — 1°  "9,  whereas  pure  atropine  is  wholly 
inactive,  it  appears  probable  that  the  transformation  is  incomplete.^ 

Hyoscyamine  forms  slender  colourless  needles,  which  sometimes 
radiate  in  groups.  In  its  solubilities  and  general  chemical  charac- 
ters it  presents  a  close  resemblance  to  atropine,  which  it  also 
simulates  in  its  physiological  effects.  The  distinctions  between 
the  bases  arc  given  on  page  254. 

Hyoscyamine  Sulphate,  BgHgSO^,  forms  small  golden-yellow  or 
yellowish  white  crystalline  scales,  or  a  yellowish  white  amorphous 
powder,  melting  at  260°  and  deliquescing  on  exposure  to  air. 

Hyoscine,    C17H23NO3. 

(See  also  page  244.)  Hyoscine  occurs,  together  with  hyoscy- 
amine, in  the  leaves  and  seeds  of  Hyoscyamus  niger  (henbane). 
The  "  amorphous  hyoscyamine "  of  commerce  appears  in  many 
cases  to  consist  chiefly  of  hyoscine.  Hyoscine  should  be  carefully 
difi'erentiated  from  atropine  and  hyoscyamine,  as  its  mydriatic 
effects  appear  to  be  more  rapid  and  powerful  than  those  produced 
by  the  latter  bases  ]  and,  taken  internally  in  doses  of  -^  grain,  it 
produces  eff'ects  distinct  from  those  of  atropine.^ 

Free    hyoscine   forms   a   thick    syrup,  having   a    close    general 

in  Atropa  belladonna  (deadly  nightshade),  in  which  it  is  sometimes  present  to 
the  exclusion  of  atropine,  which,  according  to  W  i  1 1,  is  not  un frequently  formed 
from  the  hyoscyamine  during  the  process  of  isolation.  Hyoscyamine  also  occurs 
in  association  with  atropine  in  the  seeds  of  Datura  strarnonium  (thorn-apple) ; 
Avith  hyoscine  in  the  root  of  Scopoliajaponica  and  S.  atropoides;  and  almost  alone 
in  the  root  of  S.  camiolica  and  the  leaves  and  twigs  of  Duboisia  myoporotdes. 
According  as  commercial  hyoscyamine  has  been  prepared  from  one  or  other  of 
the  above  sources,  it  is  liable  to  contain  more  or  less  of  the  associated  alkaloids. 

^  E.  Schmidt  {Pharm.  Zeit.,  1889,  page  583)  has  obtained  some  indica- 
tion of  the  formation  of  another  alkaloid  besides  atropine  in  this  reaction. 

2  Schiitte  has  recently  found  {Pharm.  Jour. ,  [3],  xxii.  429),  that  conversion 
into  atropine  occurs  when  hyoscyamine  is  kept  long  in  solution  or  in  the 
form  of  aurochloride,  or  is  repeatedly  crystallised  from  acidulated  water. 

'  The  calmative  and  sedative  effects  of  henbane,  which  distinguish  it  in 
physiological  action  from  belladonna  and  stramonium,  are  undoubtedly  due  to 
the  predominating  alkaloid,  hyoscine. 


APO-ATROPINE— SCOPOLAMINE.  251 

resemblance  to  hyoscy amine  and  atropine,  but  yielding  pseudo- 
tr opine  instead  of  tropine  on  saponification  (page  247).  The 
reverse  reaction  has  not  been  realised. 

Other  characters  of  hyoscine,  and  distinctions  from  hyoscyamine 
and  atropine,  are  given  on  page  254. 

Hyosdne  Hydrohromide  should  occur  in  colourless  rhombic 
crystals,  losing  12 "3  per  cent,  of  their  weight  when  dried  at  100°. 
With  Yitali's  test  (page  257)  it  should  give  a  violet  coloration. 
Commercial  hyoscine  hydrohromide  is  liable  to  contain  a  large 
proportion  of  the  corresponding  salt  of  scopolamine,  and, 
according  to  E.  S  c  h  m  i  d  t,  often  essentially  consists  of  this  salt.^ 

BHI  forms  pale  golden  prisms,  the  solution  of  which  is  Isevo- 
rotatory.  BHAuCl^  crystallises  in  prisms,  melts  at  200°,  and  is 
sparingly  soluble  in  water. 

Anhydro-Tropeines. 

Apo-atropine,  Cii^Hgj^NOg,  preferably  called  anhydro-atropine, 
difi'ers  from  atropine  by  the  elements  of  water,  and  hence  is  isomeric 
with  atropamine  and  belladonnine.  It  is  obtained  by  gradually 
adding  atropine  to  fuming  nitric  acid  maintained  at  about  50°  C. 
On  rendering  the  liquid  alkaline  and  extracting  with  ether,  the 
new  base  is  dissolved,  and  is  obtained  on  evaporating  the  solvent 
as  an  oil,  or  prisms  melting  at  60°-62°,  slightly  soluble  in  water, 
but  readily  in  chloroform.  Apoatropine  is  not  mydriatic  or  irritat- 
ing to  the  eye,  and  apparently  not  poisonous.  It  yields  a  crystalline 
sulphate,  sparingly  soluble  in  cold  water.  The  chloroplatinate  is 
crystalline,  and,  unlike  that  of  atropine,  only  sparingly  soluble  in 
hydrochloric  acid.  The  aurochloride  is  amorphous,  and  melts  at 
180°.  Anhydroatropine  is  hydrolysed  by  boiling  baryta-water, 
forming  tropine  and  atropic  acid. 

Atropamine,  Cj^jrHgiNOg  (page  244),  is  not  a  constant  con- 
stituent of  belladonna,  and,  owing  to  the  readiness  with  which 
it  undergoes  change,    it  is  liable  to  escape    recognition.      It  was 

^  Scopolamine,  or  Scopoleine,  C17H21NO4,  was  first  found  in  the  root  of  S. 
atropoides,  and  has  since  been  isolated  in  small  quantities  from  belladonna 
root,  stramonium  seeds,  and  D.  myoporo'ides.  In  one  case  the  mydriatic 
alkaloid  of  the  last-named  plant  consisted  essentially  of  scopolamine,  while  the 
base  from  another  sample  of  the  leaves  was  essentially  hyoscyamine.  Scopol- 
amine appears  to  contain  a  hydroxyl-group,  as  it  fornxs  an  acetyl-derivative, 
while  towards  nitrous  acid  it  behaves  as  a  tertiary  base.  By  boiling  with 
baryta  it  is  hydrolysed  with  formation  of  atropic  acid  and  a  crystalline 
base  melting  at  110°  C.  Scopolamine  hydrohromide  forms  large  glassy  crystals. 
The  aurochloride  forms  long  shining  needles,  presenting  a  peculiar  comb-like 
or  serrated  appearance  at  the  margin.  When  anhydrous,  the  aurochloride 
melts  at  214°,  and  is  nearly  insoluble  in  water. 


252        .   ATROPAMINE.   BELLADONNINE. 

isolated  by  Hesse  (Annalen,  cclxi.  87)  by  dissolving  in  acetic 
acid  the  alkaloids  left  in  the  mother-liquor  after  the  preparation 
of  atropine,  and  adding  common  salt  to  the  solution  until  a 
milky  turbidity  was  produced.  On  standing,  the  hydrochloride 
crystallises  out,  and  can  be  obtained  pure  by  recry stall isation 
from  boiling  water  after  treatment  with  animal  charcoal.  On 
treating  the  hydrochloride  with  dilute  ammonia  and  ether, 
the  atropamine  dissolves,  and  may  be  obtained  as  a  soft  colourless 
varnish  on  evaporation.  At  60°  it  forms  a  colourless,  odourless 
liquid,  which  does  not  lose  weight  at  100°.  It  is  only  sparingly 
soluble  in  water  and  petroleum  ether,  but  very  readily  in  alcohol, 
ether,  chloroform  and  benzene.  The  alcoholic  solution  is  optically 
inactive,  has  a  bitter  taste,  does  not  redden  phenolphthalein 
(distinctive  from  atropine),  but  colours  red  litmus-paper  blue  and 
neutralises  acids.  Atropamine  possesses  no  mydriatic  properties, 
but  produces  a  burning  sensation  and  inllammation  when  dropped 
into  the  eye,  whereas  apo-atropine  is  inactive. 

Atropamine  is  considered  by  Hesse  to  bear  the  same  relation 
to  hyoscine  that  anhydro-atropine  bears  to  its  parent-base,  and  is 
isomeric  with  belladonnine,  from  which  it  differs  in  ready  crystal- 
lisability  of  its  hydrochloride  and  hydrobromide,  a  fact  which 
affords  a  ready  means  of  separating  it  from  the  other  alkaloids  of 
belladonna.  If  the  hydrochloride  or  hydrobromide  of  atropamine 
be  moistened  with  a  mineral  acid,  and  warmed  or  exposed  to  sun- 
light, the  base  is  readily  converted  into  belladonnine. 

Atropamine  is  also  transformed  into  belladonnine  by  solution  in 
cold  concentrated  sulphuric  acid,  or  by  the  mere  evaporation  of  the 
solution  of  its  sulphate.  Dilute  sulphuric  acid  also  effects  the  con- 
version, but  a  preferable  plan  is  to  heat  atropamine  with  moderately 
concentrated  hydrochloric  acid  to  about  80°.  If  the  solution  be 
boiled,  or  if  baryta-water  be  employed  as  the  converting  agent,  the 
belladonnine  first  formed  undergoes  hydrolysis,  so  that  atropamine 
and  belladonnine  ultimately  yield  the  same  saponification  products. 

Belladonnine,  Ci^Hg^NOg  (page  244),  is  isomeric  with  anhydro- 
atropine  and  atropamine.^  Its  formation  from  the  latter  substance 
is  described  above.  Belladonnine  forms  a  varnish-like  mass,  very 
sparingly  soluble  in  water,  but  readily  in  alcohol,  ether,  chloro- 
form and  benzene.  The  salts  are  amorphous.  BgHgPtClg  and 
BHAuCl^  are  yellow  pulverulent  precipitates,  quite  insoluble 
in  cold  water.  Crude  belladonnine  is  said  to  contain  oxytropiney 
CgHj^^NOg,  a  crystallisable  base  melting  at  242°. 

When   belladonnine  is  boiled  with  baryta-water,  or  moderately 

*  According  to  Ladenburg  the  formula  of  belladonnine  is  C17H23NO4, 
and  it  is  converted  by  hydrolysis  into  tropic  acid  and  oxytropine. 


HOMATROPINE.  253 

concentrated  hydrochloric  acid,  it  is  hydrolysed  with  formation  of 
pseudotropine,  CgHj^NO,  and  two  acids  of  the  formula 
CgHj^Og  and  CgHgOg ;  but  as  both  these  bodies  are  amorphous 
they  appear  to  be  isomeric,  and  not  identical  with  tropic  and 
atropic  acids  respectively.  When  atropamine  or  belladonnine  is 
heated  at  100°  with  fuming  hydrochloric  acid,  pseudotropine 
and  crystallisable  atropic  acid  are  formed,  instead  of  the  fore- 
going amorphous  acids. 

Artificial  Tropeines. 

When  tropine  (page  246)  is  treated  with  benzoyl  chloride  it 
yields  benzoyl-tr opine,  C^lI>j{C2H.^.0Bz)^.CIi^,  which  is 
the  type  of  a  series  of  bodies  called  tropeines  (Ladenburg), 
having  the  constitution  of  esters  of  tropine.  The  natural 
mydriatic  alkaloids  belong  to  this  class,  and  atropine  has  actually 
been  obtained  synthetically  by  heating  tropine  with  tropic  acid. 

Bbnzoyl-tropine,  C5H7(C2H^.0C7H50)NCH3,  is  a  crystallisable 
substance  which  forms  salts  very  similar  to  those  of  atropine.  It  is 
a  powerful  local  anaesthetic,  and  when  applied  to  the  eyes  produces 
the  dilation  characteristic  of  the  natural  tropeines.  Benzoyl-pseudo- 
tr opine  occurs  naturally  in  certain  coca  leaves  from  Java  (page  287). 

Salicyl-tropine,  C^^{C^^.0.C^11^0^^CHz,  is  obtained  by 
evaporating  to  dryness  a  mixture  of  salicylic  acid  and  atropine 
with  dilute  hydrochloric  acid.  It  is  a  weak  poison,  devoid  of 
action  on  the  pupil. 

HoMATROPiNE,  C^gHgiNOg,  is  an  artificial  base  having  the  con- 
stitution of  a  lower  homologue  of  atropine.  It  is  prepared  by 
evaporating  a  mixture  of  tropine  (from  the  saponification  of 
hyoscyamine)  and  mandelic  acid,  with  dilute  hydrochloric  acid. 
Mandelic  acid  itself  is  produced  by  the  action  of  hydrochloric  acid 
on  amygdalin,  the  glucoside  of  almonds.  It  is  the  lower 
homologue  of  tropic  acid,  and  has  the  constitution  of  a  phenyl- 
glycollic  acid: — 

Mandelic  acid.  Tropic  acid. 

Homatropine  crystallises  from  absolute  ether  in  prisms  which 
melt  at  98°  C.  It  is  very  deliquescent,  and  hence  is  usually 
obtained  as  a  syrup.  It  dissolves  sparingly  in  water,  but  freely 
in  ether  and  chloroform. 

Homatropine  behaves  like  atropine  with  Gerrard's  test,  but  with 
Yitali's  test  (page  257)  it  yields  a  yellow  instead  of  a  violet 
coloration.     With  Mayer's  reagent  the  salts  yield  a  white,  curdy 


254 


REACTIONS   OF  TROPEINES. 


precipitate,  and  with  picric  acid  a  yellow  precipitate  soon  becoming 
crystalline. 

Homatropine  resembles  atropine  in  its  general  physiological 
effects,  but  is  less  toxic,  and  in  small  doses  is  a  true  hypnotic. 
It  dilates  the  pupil  as  powerfully  as  atropine,  but  the  effect  sub- 
sides far  more  rapidly,  and  hence  the  base  has  proved  valuable  in 
ophthalmic  surgery. 

Homatropine  Sulphate  crystallises  in  silky  needles.  The  hydro- 
chloride is  crystallisable  and  very  soluble.  The  chloroplatinate  is 
deposited  from  concentrated  solutions  in  fine  crystals.  BHAuCl^ 
is  described  on  next  page. 

HomMropine  Hydrohromide,  CjgHgiNOg,  HBr,  crystallises  in  non- 
deliquescent,  fiat  rhombic  prisms  or  plates  which  form  wart-like 
aggregations.  According  to  the  British  Pharmacopoeia  (Additions, 
1890)  it  is  a  white  crystalline  powder  or  aggregation  of  minute  pris- 
matic crystals,  soluble  in  6  parts  of  cold  water  and  133  of  alcohol.^ 

Detection  and  Determination  of  Tropeines. 

Atropine  and  the  allied  bases  present  a  close  general  resemblance, 
alike  in  their  physical,  physiological,  and  chemical  characters.  The 
following  table  shows  the  principal  distinctions  between  them : — 


Atropine. 


Hyoscyamine. 


Hyoscine. 


Appearance, 

Melting-point, "  C. 
Optical  activity, 


Keaction  of  free 
base  with  alco- 
holic mercuric 
chloride  (page 
256), 

Characters  of  mer- 
curochloride, 

Characters  of 
platinochloride, 


Characters        of 
aurocliloride, 

Basic  product  of 
saponification, 


Needles    or     acicular 
prisms. 


114-5 

Inactive  or  feebly  leevo- 
rotatory. 


Ked  precipitate. 


Gummy  precipitate. 


Not  ppted.  from  5  per 
cent,  solutions.  On 
evaporation,  forms 
monoclinic  crystals, 
melting  at  207'. 

Lustreless ;  yellow, 
melts  at  ISS'-ISS'. 

Tropine,  melting  at 
61°-62°. 


Slender,  radiating 
needles  or  crystal- 
line powder. 

108-5 

Sd=  -21°,  in  alcoholic 
solution. 

Yellow  or  red  precipi- 
tate. 


Oil,  solidifying  to 
plates. 

Not  ppted.  from  5  per 
cent,  solutions.  On 
evaporation,  forms 
beautiful  triclinic 
crystals,  melting  at 
200°. 

Lustrous,  golden-yel- 
low scales,  melting 
at  160°-162°. 

Tropine,  melting  at 
61°-62°. 


Syrup. 


White      precipi- 
tate. 


Amorphous  or 
oily. 

Small  octohedra 
soluble  in 

water,  alcohol 
and  ether-alco- 
hol. 

Yellow  prisms, 
melting  at  198°- 
200°. 

Pseudotropine, 
melting  at  106*. 


•^  "  If  2  minims  of  chloroform  be  shaken  with  10  minims  of  a  10  per  cent, 
aqueous  solution,  and  chlorine- water  be  cautiously  added,  the  chloroform  will 
assume  a  brownish  colour.     A  2  per  cent,  aqueous  solution  is  not  precipitated 


AUROCHLORIDES   OF  TROPEINES.  266 

The  reactions  of  the  tropeines  with  auric  chloride  form  the  best 
distinctions  between  them.  Atropine  aurochloride  is  thrown  down 
from  dilute  solutions  as  an  amorphous  or  oily  precipitate  which 
gradually  becomes  crystalline.  Under  the  microscope  it  appears  in 
rosettes  and  other  very  characteristic  forms.  It  melts  under  hot 
water,  and  is  deposited  from  its  solution  in  boiling  water  acidu- 
lated with  hydrochloric  acid  in  minute  crystals,  which  are  lustreless 
after  drying,  and  melt  at  135°- 138°.  Hyoscyamine  aurochloride  is 
precipitated  in  brilliant,  irregular,  golden-yellow  scales,  appearing 
under  the  microscope  in  quadratic  forms.  It  retains  its  lustre 
when  dry,  and  melts  at  160°— 162°.  Hyoscine  aurochloride  cTjstal- 
lises  in  yellow  prisms  which  melt  at  198°-200°,  and  are  less 
soluble  and  less  lustrous  than  the  hyoscyamine  salt.  Homatropine 
aurochloride  is  at  first  oily,  but  soon  crystallises  in  prismatic  forms. 
Sco2^olamine  aurochloride  is  described  on  page  251. 

Ladenburg  employs  the  aurochlorides  to  separate  the  tropeines 
from  each  other.  The  atropine  salt  is  the  most  insoluble  and  in 
fractional  precipitation  is  thrown  down  first,  while  the  hyoscyamine 
salt  is  the  most  readily  soluble.  The  alkaloids  may  be  recovered 
by  decomposing  the  aurochlorides  with  sulphuretted  hydrogen, 
adding  ammonia  to  the  filtrate,  and  agitating  with  chloroform 
or  ether. 

The  foregoing  properties  and  reactions  are  almost  the  only 
ones  afifording  fairly  sharp  distinctions  between  atropine  and  its 
isomers.  The  following  reactions  are  (when  not  otherwise  stated) 
common  to  the  three  bases,  and  distinguish  them  from  other 
alkaloids. 

a.  By  far  the  most  delicate  test  for  the  tropeines  is  their  power 
of  producing  rtiydriasis  or  dilation  of  the  pupil  of  the  eye. 
Dilation  from  the  application  of  a  solution  weaker  than  1  in  500 
causes  little  inconvenience  to  the  human  eye,  but  solutions  far 
weaker  produce  the  effect  quite  distinctly,  and  even  powerfully, 
and  the  eye  of  a  young  cat,  dog,  or  rabbit  is  to  be  preferred.  In 
making  such  an  experiment,  an  aqueous  solution  must  be  prepared 
either  of  the  free  alkaloid  or  its  sulphate  or  acetate.    The  solutions 

by  the  cautious  addition  of  a  solution  of  ammonia  previously  diluted  with 
twice  its  volume  of  water.  About  a  tenth  of  a  grain  moistened  with  2  minims 
of  nitric  acid,  and  evaporated  to  dryness  on  the  water-bath,  yields  a  residue 
which  is  coloured  yellow  by  an  alcoholic  solution  of  potash.  If  about  a  tenth 
of  a  grain  be  dissolved  in  a  little  water,  and  the  solution  be  made  alkaline  with 
ammonia  and  shaken  with  chloroform,  the  separated  chloroform  will  leave  on 
evaporation  a  residue  which  will  turn  yellow,  and  finally  brick-red,  when 
wanned  with  about  15  minims  of  a  solution  of  2  grains  of  perchloride  of  mer- 
cury in  100  minims  of  proof  spirit." — British  Fharmacopceia  (Additions,  1890). 


256  REACTIONS  OF  TKOPEINES. 

should  be  neutral  or  only  feebly  alkaline,  not  strongly  contami- 
nated even  with  neutral  salts,  and  not  alcoholic.  A  drop  or  two  of 
such  a  solution  is  placed  by  means  of  a  pipette  or  glass  rod  on  one 
of  the  eyes,  and  the  size  of  the  pupil  compared  with  that  of  the 
fellow-eye  from  time  to  time.  E.  R.  Squibb  {Ephemeris,  ii.  855) 
states  that  distinct  mydriasis  is  produced  by  a  solution  of 
0"000000427  gramme  of  atropine  sulphate  in  less  than  an  hour. 
Such  an  intense  effect  is  quite  peculiar  to  atropine  and  its  isomers 
(hyoscine  is  even  more  powerfully  mydriatic),  but  more  or  less 
dilation  of  the  pupil  is  also  produced  by  cocaine  and  preparations  of 
hemlock  (conine)  and  digitahs.  Aconitine  has  a  variable  effect,  and 
nicotine  is  said  first  to  dilate  and  then  to  contract  the  pupil. 
Certain  ptomaines  exert  a  mydriatic  effect. 

b.  Free  atropine,  as  obtained  by  evaporating  its  chloroformic  or 
ethereal  solution  (after  liberation  of  the  alkaloid  from  one  of  its 
salts  by  ammonia),  gives  a  red  colour  with  phenolphthalein.  This 
reaction  is  common  to  hyoscyamine  and  hyoscine,  and  is  also  pro- 
duced by  the  artificial  base  homatropine,  but  is  not  given  by  any 
other  alkaloid  in  common  use  (except,  according  to  P 1  u  g  g  e,  the 
volatile  bases  conine  and  nicotine).  Fliickiger,  who  first 
observed  the  peculiar  behaviour  of  the  tropeines  with  phenol- 
phthalein (Pliarm.  Jour.,  [3],  xvi.  601),  recommends  that  a  minute 
quantity  of  the  alkaloid  to  be  tested  should  be  placed  on  phenol- 
phthalein paper,  which  is  then  wetted  with  strong  alcohol.  I^o 
coloration  will  be  produced  at  first,  but  on  allowing  the  alcohol  to 
evaporate,  and  touching  the  alkaloid  with  a  drop  of  water,  a  bril- 
liant red  coloration  will  appear.  On  adding  alcohol  the  colour  is 
destroyed,  but  appears  again  as  the  spirit  evaporates.^ 

c.  When  a  solution  of  mercuric  chloride  in  proof-spirit  is 
cautiously  added  to  free  atropine  (as  obtained  by  evaporation  of  a 
chloroform  solution  after  liberation  of  the  alkaloid  by  ammonia), 
avoiding  excess,  a  red  precipitate  is  produced.  A.  W.  G  e  r  r  a  r  d, 
who  first  described  this  reaction  {Fharm.  Jour.,  [3],xiv.  718),  states 
that  the  precipitate  consists  of  mercuric  oxide  (with  a  trace 
of  mercurous  oxide),  and  expresses  the  reaction  by  the  following 
equation:— 2  Ci^Hgs^^Og  -f  HgClg  +  H^O  =  HgO  -|-  2Ci7H23]S^03,HCl. 
The  atropine  hydrochloride  reacts  with  an  additional  quantity  of 
mercuric  chloride  to  form  the  double  chloride  BHCl,2HgCl2,  which 
separates  in  crystalline  tufts  when  the  liquid  is  allowed  to  stand 
for  a  few  hours.  In  a  more  recent  paper  {Pharm.  Jour.,  [3],  xxi. 
898)  Gerrard  has  modified  and  more  precisely  defined  the  method 
of  making  the  test  as  follows :— 0*1    grain  of   the  free  alkaloid 

^  This  behaviour  is  peculiar.     Caustic  alkalies  react  perfectly  with  phenol 
phthalein  in  alcoholic  solution. 


gereard's  test  for  atropine.       257 

(extracted  from  a  salt  by  ammonia  and  chloroform)  is  placed  on  a 
watch-glass  or  in  a  test-tube,  and  20  minims  of  a  2  per  cent, 
solution  of  mercuric  chloride  in  proof-spirit  gradually  added.  A 
red  coloration  is  yielded  at  once  by  atropine.  Hyoscyamine  at  first 
becomes  yellow,  then  darkens  a  little,  and  finally,  on  heating,  a 
well-marked  red  precipitate  is  formed.  If  a  large  excess  of  hyoscy- 
amine be  used,  merely  a  yellow  precipitate  is  formed,  while  with  a 
large  excess  of  the  reagent  no  precipitation  occurs.^  Homatropine 
(page  253)  also  yields  a  red  precipitate  under  the  conditions  of 
the  test ;  but  hyosdne  gives  neither  a  red  nor  a  yellow  coloration 
or  precipitate,  and  hence  is  sharply  distinguished  from  the  other 
tropeines.  Gerrard  found  no  red  or  yellow  precipitate  to  be  pro- 
duced by  strychnine,  brucine,  morphine,  codeine,  veratrine,  aconi- 
tine,  conine,  gelsemine,  caffeine,  cinchonine,  cinchonidine,  quinine 
or  quinidine ;  though  most  of  these  bodies  gave  white  precipitates, 
which  in  the  cases  of  codeine  and  morphine  became  pale  yellow  on 
heating.  This  behaviour  has  been  confirmed  bySchweissinger 
(Arch.  Pharju.,  [3],  xxii.  827),  who  also  states  that  cocaine  gives  a 
white  precipitate  (only  appearing  in  strong  solutions  and  soluble  on 
warming)  and  scoparine  a  yellow  precipitate  with  mercuric  chloride  ; 
while  strychnine,  caffeine,  arbutine,  sparteine  and  condurangine 
are  stated  to  yield  no  reaction.  Schweissinger  suggests  that  the 
test  might  be  made  quantitative  for  atropine  by  determining  the 
mercuric  oxide  precipitated  ;  but  this  would  only  be  possible  in  the 
absence  of  alkaloids  or  other  substances  giving  precipitates  of 
any  kind  with  mercuric  chloride.  The  value  of  Gerrard's  test  has 
also  been  confirmed  by  FlUckiger  {Pharm.  Jour.,  [3],  xvi.  601), 
who  found  cocaine  to  give  a  pure  white  precipitate  which  very  soon 
turned  red. 

d.  Gerrard  has  also  observed  {Pharm.  Jour.,  [3],  xvi.  762)  the 
liberation  of  m  e  r  c  u  r  o  u  s  oxide  from  calomel  and  other 
mercurous  salts  by  the  action  of  atropine.  If  atropine  be  dissolved 
in  alcohol,  and  four  measures  of  water  added,  the  solution  will 
immediately  precipitate  black  mercurous  oxide  from  a  solution  of 
mercurous  nitrate  free  from  excess  of  acid.  This  is  best  prepared 
by  adding  caustic  soda,  drop  by  drop,  to  a  solution  of  mercurous 
nitrate  until  a  slight  permanent  precipitate  is  produced,  and  then 
filtering. 

e.  D.  V  i  t  a  1  i  has  observed  that  if  a  minute  quantity  of  solid 
atropine  be  treated  with  a  drop  of  fuming  nitric  acid,  the  liquid 

^  Harnack  {Chcm.  ZeiL,  xi,  52)  disputes  the  identity  of  hyoscyamine  and 
duboisine,  and  states  that  the  former  gives  a  clear  solution  witli   Gerrard's 
veagent,  a  slight  turbidity  appearing  on  continued  heating,  while  duboisine 
gives  a  white  turbidity  immediately,  and  on  warming  a  white  precipitate. 
VOL.  III.  PART  II.  R 


258  VITALI'S  TEST. 

evaporated  at  100°,  and  the  residue  when  cool  touched  with  a 
drop  of  a  freshly-prepared  solution  of  caustic  potash  in  absolute 
alcohol,  a  magnificent  violet  coloration  is  produced,  which  slowly 
changes  to  dark  red  and  ultimately  disappears,  but  can  be  repro- 
duced by  adding  more  alcoholic  potash.  The  violet  reaction  is 
almost  jieculiar  to  atropine  and  its  isomers,  and  is  said  to  be 
produced  by  O'OOOl  milligramme  of  the  alkaloid.  Out  of  some 
sixty  alkaloids  examined  no  others  were  found  to  give  a  violet 
coloration..  The  coloration  is  not  produced  if  aqueous  potash  be 
substituted  for  the  alcoholic  solution.  Strychnine  gives  a  red, 
brucine  a  greenish,  and  homatropine  a  yellow  colour  when  simi- 
larly treated.  Arnold  {Arch.  Pharm.,  1882,  page  564)  modifies 
the  test  by  moistening  the  alkaloid  with  strong,  cold  sulphuric  acid, 
and  then  adding  a  fragment  of  sodium  nitrite.  With  atropine  a 
yellow  colour  is  produced,  which,  on  applying  alcoholic  potash, 
changes  to  reddish  violet  and  then  to  pale  rose.  Strychnine  gives 
an  orange-red  colour,  but  homatropine  behaves  like  atropine. 
Alkaloids  which  yield  strong  colorations  before  the  application  of 
the  alcoholic  potash  (e.g.,  morphine,  narcotine,  narceine)  render  the 
test  inapplicable.  Fluckiger  (Pharm.  Jour.,  [3],  xvi.  601) 
recommends  that  1  milligramme  of  atropine  and  about  the  same 
quantity  of  sodium  nitrate  should  be  rubbed  together  with  a  glass 
rod,  the  end  of  which  has  been  moistened  with  a  very  little  con- 
centrated sulphuric  acid.  A  saturated  solution  of  caustic  soda  in 
absolute  alcohol  is  then  added  drop  by  drop ;  when  in  presence  of 
atropine  a  red  or  violet  colour  will  be  produced.  When  sodium 
nitrite  is  substituted  for  the  nitrate  in  the  above  test,  an  orange 
mixture  is  obtained,  which,  on  dilution  with  a  strong  aqueous  solu- 
tion of  caustic  soda,  turns  in  succession  to  red,  violet  and  lilac. 

E.  Beckmann  {Arch.  Pharm.,  [3],  xxiv.  481)  has  pointed 
out  that  veratrine  behaves  somev/hat  similarly  to  atropine  with 
Vitali's  test ;  but  states  that  with  nitrous  acid  or  a  nitrite  instead  of 
nitric  acid,  and  aqueous  instead  of  alcoholic  potash,  atropine  gives 
a  reddish  violet  coloration,  and  veratrine  a  yellow  one. 

/.  When  atropine  is  heated  to  the  boiling-point  with  a  mixture 
of  equal  measures  of  glacial  acetic  and  strong  sulphuric  acids  no 
coloration  is  produced ;  but  after  a  time  the  liquid  exhibits  a  well- 
marked  yellowish  or  brownish  green  fluorescence.  After  cooling, 
the  liquid  has  a  pleasant  aromatic  odour  in  addition  to  that  of 
acetic  acid.  The  behaviour  of  other  tropeines  with  this  test,  which 
is  due  to  E.  Beckmann,  does  not  appear  to  have  been  recorded. 
Veratrine  gives  a  similar  brownish  fluorescent  liquid,  but  during  the 
previous  heating  the  solution  acquires  an  intense  cherry-red  colour. 

g.  According  to  A.  W  y  n  t  e  r  B 1  y  t  h,  if  a  particle  of  atropine  be 


REACTIONS  OF  TROPEINES.  259 

treated  with  a  few  drops  of  concentrated  baryta  solution,  the  liquid 
evaporated  to  dryness,  and  the  residue  strongly  heated,  an  agreeable 
odour  resembling  that  of  hawthorn-blossom  will  be  perceived. 

h.  According  to  the  German  Pharmacopoeia,  if  at  least  0*001 
gramme  of  atropine  sulphate  be  heated  in  a  small  test-tube  until 
white  vapours  appear,  and  1"5  gramme  (  =  0'8  c.c.)  of  sulphuric 
acid  be  then  added,  and  the  heating  continued  until  the  mixture 
begins  to  turn  brown,  on  then  adding  2  c.c.  of  water  an  agreeable 
odour  will  be  perceived ;  and  on  further  adding  a  crystal  of 
potassium  permanganate,  the  odour  of  bitter-almond  oil  will  be 
obtained. 

i.  A  saturated  solution  of  bromine  in  hydrobromic  acid  ^  gives 
with  atropine  and  its  salts,  even  in  very  dilute  solutions  (1 :  10,000), 
a  yellow  amorphous  precipitate,  which  in  a  short  time  becomes 
crystalline.  The  precipitate  from  somewhat  strong  solutions  of 
the  alkaloid  disappears  after  a  time,  but  is  immediately  reproduced 
on  adding  more  of  the  reagent.  The  precipitate  is  insoluble  in 
acetic  acid,  and  only  very  sparingly  soluble  in  a  large  excess  of 
the  mineral  acids  or  fixed  caustic  alkalies.  It  is  even  produced 
from  a  solution  of  atropine  in  concentrated  sulphuric  acid.  The 
microscopic  appearance  of  the  precipitate  is  highly  characteristic, 
exhibiting  under  a  magnifying  power  of  75  to  125  diameters 
lanceolate,  leaf-like  crystals,  grouped  together  like  the  petals  of  a 
flower.  These  forms  may  be  obtained  by  the  spontaneous  evapora- 
tion of  a  drop  of  liquid  containing  only  ^3^0^  grain  of  atropine. 
If  not  produced,  a  drop  of  water  should  be  added,  and  evaporation 
repeated.  T.  G.  W  0  r  m  1  e  y,  who  is  the  observer  of  the  reaction, 
considers  the  formation  of  the  crystals  quite  characteristic  of 
atropine  or  hyoscyamin^-.  Most  alkaloids  give  yellow  precipitates 
with  Wormley's  reagent,  but  all  these  deposits,  except  those  pro- 
duced by  atropine,  hyoscyamine  and  meconin,  remain  amorphous ; 
and  that  produced  by  the  last-named  substance  has  quite  a  different 
microscopic  appearance  from  those  formed  by  the  mydriatic  alkaloids. 
The  behaviour  of  hyoscine  with  Wormley's  reagent  has  not  been, 
recorded. 

./.  A  solution  of  iodine  in  iodide  of  potassium  throws  down,  from 
solutions  of  atropine,  hyoscyamine  and  hyoscine,  acidulated  with 
hydrochloric  acid,  the  whole  of  the  alkaloid  as  a  reddish  brown  or 
dark  green  amorphous  precipitate  of  the  tri-iodide,  insoluble  in 
acetic  acid,  but  somewhat  affected  by  other  acids.  Dunstan  and 
Ransom  (Pharm.  Jour.,  [3],  xiv.  625)  recommend  the  reagent  for 

^  Wormley  states  that  in  tlie  absence  of  liydrobroniic  acid,  a  solution  of 
bromine  in  alcohol  may  be  used.  A  solution  in  hydrochloric  acid  would 
appear  preferable. 


260  REACTIONS  OF  TROPEINES. 

the  purification  and  determination  of  atropine  and  its  isomers.  For 
this  purpose  they  dissolve  the  alkaloid  in  dilute  hydrochloric  acid, 
and  add  excess  of  a  strong  solution  of  iodine  in  potassium  iodide. 
The  precipitate  at  once  agglomerates,  and  is  filtered  off",  slightly 
washed  with  the  solution  of  iodine,  and  then  decomposed  by 
pouring  on  the  filter  a  solution  of  sodium  thiosulphate,  which 
dissolves  it  to  a  colourless  h'quid,  from  which  the  alkaloid  is 
recovered  by  addition  of  ammonia  and  agitation  with  chloroform. 

k.  Mayer's  reagent  precipitates  atropine  and  its  isomers  from 
solutions  not  too  dilute,  and  has  been  employed  with  limiteil 
success  for  their  quantitative  determination.  The  characters  of 
the  precipitate  and  the  best  method  of  operating  have  already  been 
fully  described  (page  140  et  seq.). 

I.  Potassio-iodide  of  bismuth  and  potassio-iodide  of  cadmium 
precipitate  atropine  from  highly  dilute  solutions.  Their  reactions 
with  the  isomeric  alkaloids  have  not  been  recorded. 

m.  Phosphomolybdic  and  phosphotungstic  acids  precipitate 
atropine  and  its  isomers  from  somewhat  dilute  solutions,  and  are 
of  service  for  concentrating  the  alkaloids  and  separating  them  from 
other  organic  matter. 

n.  Am  alcoholic  solution  of  picric  acid  yields  a  yellow  amorphous 
precipitate  in  solutions  of  atropine  which  are  not  too  dilute.  The 
precipitate  becomes  crystalline  after  a  time,  and  appears  under  the 
microscope  in  highly  characteristic  forms.  With  hyoscyamine, 
picric  acid  yields  an  oily  precipitate,  rapidly  solidifying  to  right- 
angled  laminae,  very  similar  to  those  formed  by  atropine  picrate. 

The  reactions  of  atropine  and  its  isomers  with  other  reagents  are 
not  characteristic.  Potassium  iodide,  thiocyanate,  ferrocyanide, 
ferricyanide  and  chromate  fail  to  precipitate  even  concentrated 
solutions  of  these  alkaloids. 

Atropine  and  its  allies  are  not  removed  from  acidulated  solutions 
by  agitation  with  immiscible  solvents.  From  solutions  rendered 
alkaline  by  ammonia,  or  an  alkali-metal  carbonate,  they  are  readily 
and  completely  extracted  by  chloroform,  and  with  less  facility  by 
ether.  The  separated  solution  may  be  evaporated,  and  the  residue 
dried  without  loss  at  100°.  The  bases  thus  isolated  are  distin- 
guished from  all  other  well-known  alkaloids  by  their  power  of 
reddening  phenolphthalein  (test  h),  and  (with  the  exception  of 
hyoscine)  giving  a  red  precipitate  when  warmed  with  an  alcoholic 
solution  of  mercuric  chloride  (test  c).  The  alkaloidal  residue  may 
be  titrated  with  standard  hydrochloric  acid,  using  litmus  or  methyl- 
orange  as  an  indicator,  and  further  purified,  if  desired,  by  con- 
verting the  resultant  hydrochlorides  into  the  tri-iodides  (test  e), 
and  recovering  the  alkaloids  from  the  precipitates. 


POISONING   BY   ATROPINE.  261 

TOXICOLOGICAL  DETECTION  OF  ATROPINE  AND  ITS  AlLIES. 

Atropine,  hyoscyamine  and  hyoscine  are  all  higlily  poisonous. 
Cases  of  poisoning  by  the  pure  alkaloids  are  rare,  but  both  criminal 
and  accidental  poisoning  by  the  plants  of  which  they  are  the 
active  principles  have  been  frequent ;  and,  in  India,  poisoning  by 
stramonium  has  achieved  the  position  of  a  profession. 

The  symptoms  of  poisoning  by  atropine  and  its  isomers  are  thus 
described  by  A.  Swaine  Taylor : — Heat  and  dryness  of  the  mouth 
and  throat,  nausea,  vomiting,  giddiness,  indistinct  or  double  vision, 
delirium,  great  excitement  and  restlessness,  convulsions  followed  by 
drowsiness,  stupor,  and  lethargy.^  The  pupils  are  much  dilated 
and  the  eyes  insensible  to  light.  Occasionally  the  pupils  are 
contracted  during  sleep,  although  dilated  in  the  waking  state. 
The  symptoms  often  come  on  very  soon  after  taking  the  poison, 
while  recovery  may  be  delayed  for  several  days,  or  even  weeks. 
The  symptoms  of  poisoning  by  stramonium  are  very  similar  to 
those  produced  by  belladonna  and  hyoscyamus,  but  more  severe. 
Ringing  in  the  ears,  dryness  of  the  throat,  and  flushed  face  are  early 
symptoms.  Delirium  of  a  violent  kind,  with  spectral  illusions, 
comes  on  rapidly,  and  the  pupils  are  widely  dilated.  There  is 
often  paralysis  of  the  lower  extremities. 

The  post-mortem  indications  of  poisoning  by  atropine  and  its 
isomers  are  not  characteristic,  except  that  the  pupils  are  dilated. 
The  brain  and  its  membranes  are  found  congested.  AYhere  solid 
parts  of  a  solanaceous  plant  have  been  eaten  the  fragments  may 
often  be  found  in  the  stomach,  and  identified  by  their  botanical 
and  microscopic  characters. 

The  detection  of  atropine  and  its  isomers  in  cases  of  poisoning 
may  be  effected  by  the  Stas-Otto  process.  Heating  with 
alkalies  or  mineral  acids  must  be  avoided,  or  the  alkaloid  may 
undergo  hydrolysis  (page  245).  Hence  tartaric  or  acetic  acid  should 
be  used  to  acidify  the  matters  to  be  examined.  Ammonia  or  a 
carbonate  of  alkali-metal  should  be  used  to  liberate  the  alkaloid, 
and  ether  or  (preferably)  chloroform  employed  for  its  extraction. 
The  tests  most  serviceable  for  the  recognition  of  atropine  and  its 
isomers  in  cases  of  poisoning  are : — 

1.  The  dilation  of  the  pupil  (page  255). 

2.  The  reactions  of  the  free  alkaloid,  as  obtained  in  the  chloro- 
form-residue, with  phenolphthalein  and  a  spirituous  solution  of 
mercuric  chloride. 


^  The  symptoms  of  atropine  poisoning,  especially  in  children,  are  not  unlike 
those  of  scarlet  fever.  Some  cases  resemble  rabies,  and  the  garrulous  delirium 
and  hallucinations  of  an  adult  are  very  similar  to  those  of  delirium  tremens. 


262  CHRYSATROPIC   ACID. 

3.  The  reaction  of  a  solution  of  the  alkaloid  with  bromine  (page 
259),  and  the  microscopic  appearance  of  the  precipitate. 

4.  The  production  of  a  violet  colour  by  Vi tali's  test  (page  257). 

5.  The  evolution  of  an  agreeable  odour  when  the  alkaloid  is 
evaporated  to  dryness  with  baryta-water,  and  the  residue  heated. 

6.  The  microscopic  appearance  of  the  picrate. 

Atropine  does  not  appear  to  suffer  change  in  the  body  after 
death.  It  has  been  detected  after  a  considerable  interval  of  time. 
Ptomaines  having  a  mydriatic  action  have  been  met  with. 

Belladonna,  Henbane,  and  Stramonium. 

Atropa  belladonna  or  deadly  nightshade,^  Hyoscyamns  niger  or 
henbcine,^  and  Datura  stramonium  or  thorn-apple  ^  are  the  three 
chief  sources  of  the  tropeines ;  but  these  or  similar  alkaloids  are 
found  in  a  number  of  allied  species,  and  the  poisonous  alkaloid 
solanine  occurs  in  all  the  species  of  Solanum,  as  well  as  in 
other  members  of  the  SoJanacece.^ 

In  addition  to  the  alkaloids,  which  are  probably  in  combination 
with  malic  acid,  belladonna  root  contains  cellulose,  starch, 
sugar,  inulin,  asparagin,  fatty  matter,  a  fluorescent  substance,^  and 

1  French,  la  Belladone,  la  Morelle  furieuse ;  German,   TollkirscJie,  Wolfs- 
kirsche,  Tollkraut. 

2  French,  la  Jusquiame;  German,  BilsenkratU. 
^  French,  Stramoine  ;  German,  Stcchayfel. 

^  A  minute  proportion  of  an  alkaloid,  apparently  identical  with  hyoscyamine, 
has  been  found  in  lettuce  by  T,  S.  Dymon  d  {Troc.  Cliem.  Soc,  1891,  p.  165). 

^  The  fluorescent  substance  contained  in  belladonna  root,  and  present  also 
in  the  leaves  and  stalk,  is  called  by  H.  K  u  u  z  {Arch.  PJMrm,,  [3],  xxiii.  722) 
chrysatropic  acid,  and  is  said  to  have  the  formula  Cj.jHioOj.  H.  Paschkis 
{Arch.  Pharm.,  [3],  xxiii.  541 ;  xxiv.  155)  has  isolated  what  is  apparently  the 
same  body  from  the  berries  of  ripe  belladonna,  and  ascribes  to  it  the  formula 
C10H8O4.  He  considers  it  identical  with  the  scopoletin  obtained  by 
Eykman  from  Scopolia  japonica.  It  forms  pale  yellow,  rhombic  prisms  or 
needles,  melting  at  198°-201°,  and  subliming  without  decomposition  when  care- 
fully heated.  It  dissolves  in  about  80  parts  of  hot  water,  more  sparingly  in 
cold  water  and  ether,  but  readily  in  acetic  acid,  alcohol,  chloroform,  amylic 
alcohol  and  benzene.  It  is  extracted  by  the  last  three  solvents  from  its  aqueous 
solution.  The  aqueous,  alcoholic  and  ammoniacal  solutions  exhibit  a  splendid 
blue  fluorescence  when  dilute,  and  emerald-green  when  concentrated.  The 
fluorescence  is  destroyed  by  acids.  Ferric  chloride  gives  an  emerald-green 
coloration  changing  to  cobalt-blue.  Fehling's  solution  and  ammonio-nitrate 
of  silver  are  reduced  on  warming.  In  moderately  concentrated  nitric  acid  the 
substance  dissolves  with  yellow  colour,  changed  to  blood-red  by  ammonia. 
(This  reaction  resembles  that  of  se  s  c  u  1  i  n,  observed  by  Sonnenschein. ) 

Kunz  isolated  chrysatropic  acid  by  treating  the  extract  of  belladonna  with 
acid  and  agitating  with  ether.     On  evaporating  the  ether,  and  washing  the 


Woody  Roots. 

Soft  Roots. 

7-94  per  cent. 

10-28  percent. 

,       3-43       ,, 

2-20       ., 

.       4-60       „ 

3-68       „ 

.     22-53       „ 

29-87       ,, 

.     15-96       „ 

10-50       „ 

BELLADONNA.  263 

a  red  colouring-matter  called  atrosin,  which  is  also  found  in 
considerable  quantity  in  the  berries.  The  proportion  of  starch  in 
young  belladonna  roots  is  considerable,  but  it  is  present  only  to  a 
limited  extent  in  older  and  more  woody  roots,  and,  according  to  W. 
Merz,  is  almost  entirely  absent  during  summer.  The  following 
analyses  of  air-dry  belladonna  roots  are  due  to  E.  M.  Holmes : — 

Moisture, 
Soluble  ash,    . 
Insoluble  ash, 
Alcoholic  extract, 
Aqueous  extract, 

Belladonna  leaves  contain  cellulose,  chlorophyll,  alkaloidal  salts, 
fatty  and  resinous  matters,  &c.  Choline  is  present,  and,  accordinc; 
to  B  i  1 1  z,  asparagin  sometimes  crystallises  from  the  extract  after 
long  keeping,  but  the  crystals  observed  by  A  1 1  f  i  e  1  d  consisted  of 
potassium  nitrate  and  chloride.  By  dialysis,  Attfield  isolated 
potassium  nitrate,  and  square  prisms  of  an  organic  salt  of  magnesium. 
Kunz  found  O'G  per  cent,  of  succinic  acid  in  an  extract  prepared 
from  the  herbaceous  parts  of  belladonna.  Fliickiger  found  the 
ash  of  dry  belladonna  leaves  to  amount  to  1 4*5  per  cent.,  and  to 
consist  chiefly  of  the  carbonates  of  calcium  and  the  alkali-metals. 

With  regard  to  the  alkaloids  of  belladonna,  0.  Hesse 
{Annalen,  cclxi.  87)  states  that  in  his  experience  the  herb  of 
cultivated  belladonna  contains  atropine  almost  exclusively,  but  that 
it  is  associated  with  other"  alkaloids  in  the  leaves  of  wild  plants, 
and  especially  in  the  roots  of  both  kinds.  In  an  old  root,  Hesse 
found  much  hyoscy amine  but  no  atropine.  E.  Schmidt  (Pharm. 
Zeit,  1889,  page  583)  found  hyoscyamine  but  no  atropine  in  full 
grown  roots  which  had  been  kept  for  years.  In  roots  of  one  year's 
growth  he  found  both  atropine  and  hyoscyamine,  but  the  latter 
alkaloid  only  in  fresh  old  root?.  The  leaves  of  wild  belladonna 
contained  much  hyoscyamine  and  a  little  atropine,  while  the  ripe 
berries  contained  atropine  only.  E.  Schmidt  has  found  both 
hyoscyamine  and  hyoscine  in  ScopoUa  atropo'ides  and  Scopolia 
iaponica^^  and  traces  of  an  alkaloid  having  a  mydriatic  action  in 
Solanum  tuberosum,  S.  nir/rum  and  Lycium  harbarum,.  Mandra- 
gorine,  the  alkaloid  of  Mandrarjora  vernalis,  is  mydriatic  and 
possibly  isomeric  with  atropine  (page  243).     , 

crystalline  residue  with  cold  ether,  chrysatropic  acid  remained,  while  1  e  u  c  o- 
tropio  acid,  C17H32O6,  dissolved.  The  latter  is  a  bitter  substance,  crystal- 
lising in  microscopic  prisms  which  melt  at  74°. 

^  Dunstan  and  Chaston  found  the  alkaloid  of  Scopolia  cnrnioh'ca  to  consist 
of  hyoscyamine  with  a  possible  trace  of  hyoscine. 


264 


BELLADONNA. 


A.  W.  Gerrard  {Tear-Book  Pharm.,  1881,  1882,  1884)  lias 
published  a  number  of  valuable  observations  on  belladonna,  in 
which  he  found  the  following  percentages  of  alkaloid  ; — 


Age  of  Plant. 


Two  years, 
Three  years, 
Four  years, 


Wild  Plant. 

Cultivated  Plant. 

Root. 

Leaves. 

Root. 

Leaves. 

•260 

•431 

•207 

•320 

•381 

•407 

•370 

•451 

•410 

•510 

•313 

•491 

These  and  other  observations  of  Gerrard  show  that  the  leaf  of 
belladonna  is  the  part  of  the  plant  richest  in  alkaloid ;  the  root, 
fruit,  and  stem  coming  next  in  the  order  stated.^  The  results  of  A. 
B.  Lyons  {Mamial  of  Pharmaceutical  Assaying)  do  not  show 
the  same  distinction,  for  in  twelve  samples  of  (air-dried)  leaves  the 
proportion  of  alkaloids  varied  from  0*4 1  to  0*69  per  cent.,  and  in 
fifteen  samples  of  roots  from  0*47  to  1'35  per  cent.  The  extractive 
matter  in  the  leaves  (air-dried,  and  treated  with  66  per  cent, 
alcohol)  ranged  from  6'6  to  12*1  per  cent.,  and  in  the  roots  from 
2 2  "5  to  31*5  per  cent.,  with  an  average  of  about  8  per  cent,  of 
moisture.  Lyons  states  that  the  pressed  leaves  do  not  suffer 
deterioration  when  kept  for  six  years. 

R.  Kordes  found  0*58,  and  von  Gunther  0 '8 3  per  cent. 
of  alkaloid  in  belladonna  leaves,  while  L  e  f  o  r  t  gives  the  average 
yield  from  8  specimens  at  0'436  per  cent. 

As  the  general  result  of  published  investigations,  Farr  and 
"Wright  state  that  the  proportion  of  alkaloids  in  good  specimens 
of  commercial  belladonna  leaves  ranges  from  0*30  to  0*87  per 
cent.,  their  own  experiments  varying  between  0*30  and  0'90,  with 
an  average  of  0'49  per  cent.  German  leaves  are  distinctly  poorer 
in  alkaloid  and  extractive  matter  than  those  of  English  growth, 
and  hence  the  B.P.  direction  to  prepare  the  tincture  from  tl^e 
leaves  of  "plants  grown  in  Britain"  should  be  strictly  observed.  As 
one  part  of  belladonna  leaves  produces  20  parts  of  the  B.P, 
tincture,  it  follows  that  the  proportion  of  alkaloid  in  this  prepara- 
tion averages  0*025  per  cent.,  which  strength  might  advantageously 
be  adopted  as  a  standard. 

For  the  assay  of  belladonna  root,  D  u  n  s  t  a  n  and  Ransom 
(Pharm.   Jour.,    [3],   xiv.    623)    recommend    extraction    in    the 

1  The  influence  of  age  on  the  proportion  and  nature  of  the  alkaloids  of 
belladonna  has  also  been  studied  by  Schiitte  {Pharm.  Jour.,  [3],  xxii.  429). 


ASSAY   OF   BELLADONNA.  266 

following  manner:  — 20  grammes  of  the  dry  and  finely-powdered 
root  is  extracted  by  hot  percolation  with  a  mixture  of  equal 
volumes  of  chloroform  and  absolute  alcohol.^  If  an  extraction- 
apparatus  be  used  about  60  c.c.  of  the  mixture  will  be  required. 
The  solution  is  agitated  with  two  successive  quantities  of  distilled 
water,  using  25  c.c.  each  time.  The  separation  of  the  aqueous 
liquid  from  the  chloroform  occurs  promptly  and  completely  on 
warming  the  liquid  slightly.  The  chloroform  retains  nearly  the 
whole  of  the  colouring-matter,  while  the  alcohol  and  alkaloids  (as 
salts)  pass  into  the  water.^  The  aqueous  layer  is  separated,  and 
agitated  once  with  chloroform  to  remove  the  last  traces  of  colouring- 
matter;  after  which  it  is  rendered  alkaline  with  ammonia,  and 
agitated  twice  with  chloroform,  using  25  c.c.  each  time,  to  extract 
the  alkaloid.  The  separated  chloroform  is  agitated  once  with 
water  rendered  faintly  alkaline  wnth  ammonia,  and  then  evaporated, 
the  residue  being  dried  at  100°  till  constant  in  weight.  The 
alkaloid  thus  isolated  is  obtained  as  a  perfectly  transparent  fused 
mass.  It  is  soluble  in  water,  and  the  aqueous  solution  gives  pre- 
cipitates with  Thresh's,  Mayer's,  and  Sonnenschein's  reagents 
(pages  136,  138).  It  gives  a  faint  white  precipitate  with  mercuric 
chloride,  and  a  copious  white  precipitate  with  gallotannic  acid 
cautiously  added.  This  last  precipitate  is  very  readily  soluble  in 
a  slight  excess  of  the  reagent,  a  distinct  trace,  however,  invariably 
remaining  undissolved  (Farr  and  Wright).^ 

Instead  of  weighing  the  isolated  alkaloid  it  may  be  titrated 
with  standard  acid  and  litmus  (or  methyl-orange)  as  recommended 
by  Gerrard  (Year-BooJc  Pharm.,  1884,  page  447). 

D  u  n  s  t  a  n  and  Ransom  (  Year-Book  Pharm.,  1 885,  page 
391)  recommend  continuous  percolation  with  boiling  absolute 
alcohol  for  the  extraction  of  the  alkaloids  from  belladonna  leaves, 
and  they  proved  that  the  leaves  thus  treated  yielded  no  further 

^  Cliloroform  alone  extracts  the  alkaloids  very  incompletely.  Alcohol 
employed  alone  dissolves  much  extractive  matter  which  impedes  the  subse- 
quent extraction  and  purification  of  the  alkaloids.  If  rectified  spirit  instead 
of  absolute  alcoliol  be  employed  in  admixture  with  chloroform,  the  water  pre- 
sent causes  swelling  of  the  material,  and  the  progress  of  the  extraction  is 
seriously  impeded.  Dunstan  and  Ransom  proved  that  the  mixture  of  equal 
measures  of  chloroform  and  alcohol  recommended  by  them  completely  extracted 
belladonna  root,  and  that  pure  atropine  was  not  appreciably  aH'ected  by  pro- 
longed boiling  with  the  solvent. 

2  Although  Dunstan  and  Ransom  found  the  whole  of  the  alkaloids  to  pass 
into  the  aqueous  liquid,  A.  B.  Lyons  points  out  that  it  is  desirable,  as  a 
precaution,  to  make  a  small  addition  of  sulphuric  acid  to  the  water  employed. 

^  The  alkaloids  from  stramonium  behave  similarly,  probably  owing  to  the 
presence  of  a  small  quantity  of  another  (third  ?)  alkaloid. 


266  BELLADONNA  PREPARATIONS. 

quantity  of  alkaloid  when  boiled  with  dilute  hydrochloric  acid,  or 
when  mixed  with  lime  and  extracted  with  chloroform.  From  the 
extract  obtained  on  evaporating  the  alcoholic  liquid,  they  found  it 
impossible  to  remove  the  whole  of  the  alkaloid,  even  by  many 
successive  treatments  with  water  or  dilute  hydrochloric  acid. 
They  therefore  recommend  that  the  alcoholic  liquid  should  he 
diluted  considerably  with  water  acidulated  with  hydrochloric  acid, 
and  the  liquid  then  shaken  repeatedly  with  chloroform  to  remove 
the  chlorophyll  and  fat.^  From  the  liquid  thus  purified  the 
alkaloids  can  readily  be  obtained  pure  by  adding  excess  of  ammonia 
and  extracting  with  chloroform. 

A  modification  of  the  foregoing  process  is  recommended  by 
D  u  n  s  t  a  n  and  Ransom  for  the  assay  of  the  solid  extract  of 
belladonna.  Two  grammes  should  be  warmed  with  dilute  hydro- 
chloric acid  until  as  much  as  possible  is  dissolved,  when  the 
liquid  is  filtered  through  cotton  or  glass  wool,  and  the  residue  well 
washed  with  hot  dilute  hydrochloric  acid.  The  filtrate  is  repeatedly 
shaken  with  chloroform  to  remove  chlorophyll,  then  ammonia 
added,  and  the  liberated  alkaloids  extracted  with  chloroform. 

The  tincture  of  belladonna  can  also  be  assayed  by  the  foregoing 
process  after  evaporating  off  the  greater  part  o"f  the  alcohol,^  and 
the  same  remark  applies  to  the  fluid  extract.  It  is,  however,  in 
many  cases  preferable  to  treat  the  clear  liquid  at  once  with  ammonia 
and  chloroform.  On  subsequently  treating  the  separated  chloro- 
form with  dilute  sulphuric  acid,  the  colouring-matters  remain  in 

^  J.  "Williams  suggests  that  it  would  be  better  to  employ  ether  at  this 
stage  of  the  process. 

^  Farr  and  Wright  have  shown  that  the  strength  of  alcohol  used  in  ex- 
hausting the  drug  has  little  effect  on  the  proportion  of  alkaloid  in  the  tincture, 
though  it  very  greatly  affects  the  proportion  of  mucilaginous  and  colouring 
matters  extracted,  and  the  former  of  these  impede  the  separation  of  the  chloro- 
formic  and  aqueous  layers.  The  difficulty  may  be  overcome  by  evaporating 
the  tincture  to  a  syrup  and  treating  it  with  strong  alcohol,  which  precipitates 
the  mucilage,  and  the  filtrate  gives  on  evaporation  a  liquid  which  can  be 
readily  dealt  with. 

Farr  and  Wright  find  it  impossible  to  remove  the  whole  of  the  alkaloids 
of  belladonna  (and  henbane)  by  repeated  agitation  with  ether  in  presence  of 
ammonia,  at  least  20  per  cent,  of  the  total  remaining  unextracted  by  ether, 
but  recoverable  by  subsequent  agitation  with  chloroform.  Hence  ether  is  an 
unsuitable  solvent  for  extracting  mydriatic  alkaloids,  and  the  results  of 
Gerrard  and  others  who  have  used  it  are  probably  below  the  truth.  In 
fact,  Gerrard  himself  states  that  several  extractions  with  ether  are  neces- 
sary, and  that,  as  a  rule,  he  subsequently  renders  the  ammoniacal  solution 
neutral  with  citric  or  tartaric  acid,  evaporates  it  to  a  small  volume,  treats  it 
again  with  ammonia,  and  again  agitates  with  ether. 


ASSAY   OF   HENBANE. 


267 


the  chloroform,  while  the  alkaloids  can  be  recovered  in  the  pure 
state  by  rendering  the  acid  liquid  again  alkaline,  and  agitating  it 
with  chloroform. 

A.  W.  G  e  r  r  a  r  d  has  employed  substantially  the  same  process 
as  the  above  for  the  assay  of  the  root  and  leaves  of  henbane  {Pharm. 
Jour.,  [3],  xxi.  212  ;  xxii.  213).  The  substance  is  dried  at  100°, 
powdered,  and  exhausted  with  proof-spirit.  The  spirit  is  distilled 
off,  and  the  semi-fluid  extract  treated  with  water  containing  1  per 
1000  of  hydrochloric  acid,  filtered,  and  the  filtrate  further  diluted 
to  100  c.c.  The  alkaloids  are  extracted  by  ammonia  and  chloro- 
form in  the  usual  way,  purified  by  solution  in  ether,  and  agitated  with 
hydrochloric  acid ;  again  liberated  by  ammonia,  extracted  by  ether, 
and  determined  in  the  alkaloidal  residue  by  titration  with  deci- 
normal  hydrochloric  acid.     The  following  results  are  recorded  : — 


Variety  of 
Henbane. 

Part  Used. 

Where  Grown. 

Yield  of  Alkaloids 
per  1000. 

Biennial,    . 

Roots. 

Middlesex. 

1-602 

)»          • 

" 

Sussex. 

1-550 

)i          •        • 

Lincolnshire. 

1-729 

First  year's  leaf. 

Lincolnshire. 

•690 

>i 

" 

Sussex. 

•667 

• 

Middlesex. 

•592 

»i          •       • 

Second  year's  leaf, 

Middlesex. 

•672 

Sussex. 

•680 

. 

,- 

Lincolnshire. 

•656 

Annual,     . 

Leaves  and  tops. 

Leicestershire. 

•641 

>> 

11 

Surrey. 

•6S9 

,. 

Middlesex. 

•701 

Annual. 

Entire  herb. 

Germany. 

•295 

Biennial,    . 

First  year's  leaves. 

France. 

•398 

) 

(old). 

England. 

■    •ago 

•       • 

Second  year's  tops  (old). 

England, 

•451 

Gerrard's  experiments  appear  to  show  that  a  considerable  falling 
off  in  the  alkaloidal  value  of  the  leaves  occurs  with  age.  He 
considers  that  bright-coloured,  well-preserved  henbane,  whether 
annual  or  biennial,  can  be  relied  on  to  yield  good  preparations, 
while  old  and  dark-coloured  leaves,  containing  stalks  and  fruit, 
should  be  avoided.  He  regards  the  first  year's  root  of  biennial 
Hyoscyamus  niger  as  much  richer  in  alkaloids  than  the  herbaceous 
portions  of  the  plant,  but  both  as  much  poorer  than  the  respective 
parts  of  belladonna.^  Hyoscyamus  alhus  is  much  used  in  the  south 
of  Europe,  but  no  greater  strength  is  attributed  to  it. 

1  These  conclusions  are  entirely  in  opposition  to  the  experience  of  E. 
Thorey  (Dragendorft's  Quelques  Drogues  Actives),  who  found  henbane  to 
contain  alkaloid  in  greatest  quantity  in  the  leaves,  next  in  the  fruit,  then  in 
the  roots,  and  lastly  in  the  stalk.  The  substance  was  first  exhausted  with 
petroleum  spirit  to  free  it  from  fat,  then  dried,  finely  powdered,  and  extracted 


268 


STRAMONIUM. 


F.  Eansom  found  0'58  per  1000  of  pure  alkaloid  in  the 
seeds  of  biennial  henbane  grown  at  Hitchin.  Henbane  seed  is 
used  in  Germany  for  the  preparation  of  the  alkaloid. 

F  a  r  r  and  Wright  {Pharm.  Jour.,  [3],  xxii.  255)  have  proved 
that  practically  the  whole  of  the  alkaloid  of  henbane  is  contained 
in  the  tincture.  From  100  c.c.  of  tincture  (corresponding  to  12 '5 
grammes  of  the  substance),  prepared  from  different  parts  of  the 
plant,  they  obtained  the  following  weights  of  alkaloid  : — 


From  100  c.c.  of 
Tincture. 

From  100  parts  of 
Substance, 

Dried  leaves,  average, 

0-0103  grammes. 

0-0824  per  cent. 

Recently  dried  fresh  leaves. 

0-013 

0104         „ 

Seeds,        .... 

0-015 

0-120         „ 

Root-bark,          , 

0-020 

0-160         „ 

From  stramonium  seeds,  J.  D.  A.  Hartz  {Pharm.  Jour.,  [3], 
XV.  203)  obtained  0*167  per  cent,  of  alkaloid,  by  extracting  the 
fat  from  the  dried  substance  by  petroleum  spirit,  then  removing 
the  alkaloid  with  proof-spirit,  and  proceeding  in  the  usual  way. 
F  a  r  r  and  Wright  found  from  0*1 6  to  0*24  per  cent,  of  alkaloid 
in  stramonium  seeds.  E.  Schmidt  found,  in  four  samples  of 
stramonium  seed  from  different  sources,  0*25,  0*37,  0-05,  and  0*20 
per  cent,  of  total  alkaloids.  From  50  to  70  per  cent,  of  these  con- 
sisted of  pure  atropine  melting  at  115°  C.  The  remainder,  which 
was  much  more  difficult  to  crystallise,  consisted  of  hyoscyamine,  and 
probably  other  bases  and  their  decomposition-products.  But  the 
relative  proportions  of  the  alkaloids  are  probably  very  variable,  as 

with  faintly  acidified  rectified  spirit  at  a  temperature  of  80°-40°  C.  The 
alcohol  was  distilled  off,  and  the  residual  liquid  filtered.  The  filtrate  was 
purified  by  agitation  with  chloroform  or  petroleum  spirit,  then  rendered 
alkaline  with  potash  or  ammonia,  and  the  alkaloid  extracted  by  agitation  with 
chloroform.  The  following  figures,  by  Thorey,  represent  the  percentage  pro- 
portions of  alkaloids  obtained  from  the  dried  materials : — 


Part  of 
Plant. 

Plant  destitute  of  Flowers. 

Plant  in  Flower. 

Plant  in  Fruit. 

Hyosc.  albus. 

Hyosc.  niger. 

Hyosc.  albus. 

Hyosc.  niger. 

!  Hyosc.  albus. 

1 

Hj^osc.  niger. 

1868 

1869. 

1868. 

1869. 

1868. 

1869. 

1868. 

1869. 

'   1868. 

1869. 

1868. 

1869 

Seeds,      . 

... 

... 

... 

... 

1 

... 

... 

0-162 

0-172 

0-075 

0-118 

Leaves,  . 

0-588 

0-469 

0-154 

0-192 

0-359 

0-329 

0-147 

0-206 

0-211 

0  153 

0-065 

0-110 

Stalk,     . 

0  012 

... 

0  070 

0-017  ; 

0  036 

0-048 

0-032 

0  030 

0  027 

0-029 

0-009 

0  010 

Root,      . 

0  128 

0176 

0-027 

0-080 

0-146 

0-262 

0-127 

0-138 

0-106 

0-086 

0-028  [  0  056 

EXTRACT   OF   BELLADONNA.  269 

Ladenburg  found  hyoscyamine  to  prejDonderate,  and  Schiitte 
found  that  both  fresh  and  old  stramonium  seeds  yielded  chiefly 
hyoscyamine,  with  small  quantities  of  ready-formed  atropine  and 
scopolamine.  A.  B.  Lyons  {Manual  of  Pharmaceutical  Assay- 
ing) found  in  five  specimens  of  stramonium  seed  proportions  of 
alkaloid  (titrated  by  Mayer's  solution)  ranging  from  0*45  to  0"55 
per  cent.,  the  extractive  matter  yielded  to  strong  alcohol  by  the 
same  samples  varying  from  3 '3  to  7 '5  per  cent.  In  eight  samples 
of  stramonium  leaves,  Lyons  found  from  0'40  to  0*52  per  cent,  of 
alkaloid  (titrated),  and  from  19*5  to  25*3  per  cent,  of  extractive 
matter  yielded  to  spirit  of  66  per  cent.  Fair  and  Wright  ex- 
tracted from  0*12  to  0*22  per  cent,  of  alkaloid  from  stramonium 
leaves. 

R.  K  0  r  d  e  s  ("  Inaugural  Dissertation,"  Dorpat,  1888)  found  the 
following  percentages  of  alkaloid  in  the  sources  stated  : — 

Leaves.  Roots. 

Belladonna,      ....     0'61  per  cent.  0'74  per  cent 

Hyoscyanius,    .         .         .         .     015       ,,  0"13       „ 

Stramonium,    ....     0*20      ,,  0*15       ,, 

R.  Kordes  has  also  published  the  results  of  analyses  of  a  large 
number  of  tetrads  of  belladonna,  henbane  and  stramonium.-^  His 
figures  show  the  yield  of  ^extract,  the  percentage  of  water  and 
alkaloid  in  the  preparation,  and  the  proportion  of  total  alkaloid 
obtained  in  the  extract. 

Dun  Stan  and  Ransom  (Pharm.  Jowr.,  [3],  xvi.  777)  found 
the  alkaloids  in  nine  commercial  specimens  of  solid  extract  of  bella- 
donna root  to  vary  from  1"65  to  4'45  per  cent.,  the  water  ranging 
from  16'0  to  21 '6  per  cent.  They  state  that  the  extract  contains, 
besides  atropine  and  hyoscyamine  (and  possible  traces  of  another 
alkaloid),  the  fluorescent  substance  called  chrysatropic  acid  (page 
262)  and  "  much  dextrose."  This  observation  is  of  interest  in  rela- 
tion to  the  assumption  of  Schweissinger  (Pharm.  Zeit,  1886, 
page  101),  that  a  genuine  extract  of  belladonna  leaves  contains  no 
substance  capable  of  reducing  Fehling's  solution  at  a  temperature  of 
60°-70°  C,  any  reddish  turbidity  or  precipitate  being  probably 
due  to  sojDhistication  with  dextrin  or  the  extract  of  dulcamara 
or  taraxacum.  Analyses  of  various  extracts  of  belladonna  have 
been  published  by  J.  C.  Umney  {Pharm.  Jour.,  [3],  xxii.  364). 

L.  van  Itallie  recommends  that  the  extracts  of  belladonna 
and  henbane  should  be  assayed  by  treating  5  grammes  of  the  sample 
with  10  drops  of  dilute  sulphuric  acid  (1 :20),  diluting  with  water  to 
50  c.c,  and  macerating  for  some  hours.     Twenty-five  c.c.  of  a  10  per 

^  Also  analyses  of  extracts  of  conium,  cheledonium,  aconite,  nux  vomica  and 
physostigma. 


270  ECGONiNE   DERIVATIVES. 

cent,  solution  of  lead  acetate  is  then  added,  and  after  allowing  the 
precipitate  to  settle  the  liquid  is  passed  through  a  dry  filter.  From 
50  c.c.  of  the  filtrate  the  excess  of  lead  is  precipitated  by  10  c.c.  of 
dilute  sulphuric  acid  (1:10),  and  the  liquid  again  filtered.  From 
50  CO.  of  this  second  filtrate  the  alkaloids  are  then  liberated  by 
ammonia,  extracted  by  three  agitations  with  chloroform,  the  solvent 
evaporated,  and  the  residual  alkaloids  dissolved  in  spirit  and  titrated 
with  centinormal  acid. 


COCA  ALKALOIDS.^ 

The  leaves  of  Erythroxylon  coca  and  allied  species  ^  contain  a 
number  of  closely-allied  alkaloids,  all  of  which  appear  to  be 
derivatives  of  e  c  g  o  n  i  n  e,  CgH^gNOg,  a  base  which  E  i  n  h  o  r  n 
and  Hesse  regard  as  a  derivative  of  tetrahydropyridine 
(pages  106,  164),  and  to  which  they  assign  a  constitution  expressed 
by  the  following  formula  : — 

^„  j  CH2.CH[CH(OH)CH2.CO.OH]  \^  r.^ 
^^2|cH:CH  |iN.v.±i3 

According  to  this  formula,  ecgonine  is  methyltetrahydro- 
pyridyl-/3-hydroxy  propionic  acid.  When  heated 
with  baryta,  it  splits  into  carbon  dioxide  and  isotropine,  and 
hence  may  be  regarded  as  isotropyl-carboxylic  acid. 

Me.  CgHyN.CHlOH).  CHa-  COOH  =  COg  +  Me.05H7N.CH(OH).  CHa-  H 
Ecgonine.  Isotropine. 

The  relation  between  ecgonine  and  isotropine  (and  therefore 
between  cocaine  and  atropine)  is  equally  evident  from  a  comparison 
of  the  formula  of  their  respective  anhydrides :  — 

Anhydro-ecgonine.  Tropidine. 

The  hydrogen  of  the  hydroxyl-group  of  ecgonine  can  be  substi- 
tuted by  acetyl,  benzoyl,  cinnamyl,  and  other  acid-radicals.  Thus  : — 

Benzoyl-ecgonine,     Me.C5H7KCH(O.C7H50).CH2.COOH 
Cinnamyl-ecgonine,  Me.C5H7N.CH(O.C9H70).CH2.COOH 

^  The  author  is  indebted  to  Dr  B.  H.  Paul  and  Mr  A.  J.  Cownley  for 
perusal  and  correction  of  this  section. 

2  Upwards  of  eighty  species  of  the  genus  Erythroxylon  are  found  in  Brazil 
[Pharm.  Jour.,  [3],  xvii.  507);  but  most  of  these  species,  other  than  E.  coca, 
yield  very  little  cocaine  {Pharm.  Jour.,  [3],  xix.  70). 


BASES   OF   COCA.  271 

By  heating  those  compounds  with  alkyl  iodides,  the  correspond- 
ing esters  may  be  obtained  : — 

Methyl  beuzoyl-ecgonine  (cocaine),  MeC5H7N.CH(O.C7H50).CH2.CO.OCH3 
Ethyl beiizoyl-ecgonme(homococaine),  MeC5H7N.CH(O.CVHgO).CHo.CO.OC2H5 
Methyl  cinuarayl-ecgouiiie,    .         .        MeU5H7KCH(O.C9H70).CH,.CO.OCH8 

Methyl  benzoyl-ecgonine  or  cocaine  is  the  most  important 
and  characteristic  of  the  bases  of  coca.  Methyl  cinnamyl-ecgonine 
occurs  occasionally,  in  small  quantity,  in  the  broad-leaved  South 
American  coca,  and  regularly,  and  sometimes  in  considerable 
quantity,  in  Truxillo  coca. 

When  dibasic  acids  react  on  ecgonine,  bodies  of  more  complex 
constitution  result.  One  of  these  (the  methyl-ester  of  a  substance 
polymeric  with  cinnamic  acid,  called  by  Hesse  cocaic  acid, 
CigHigO^,  and  by  Liebermann  y-isatropic  or  truxillic 
acid),  is  the  c o c a m i n e,  CggH^^NoOg,  of  Hesse,  and  the 
isatropy  1-cocaine  or  a-truxilline  of  Liebermann. 
The  next  higher  homologue  of  cocayl-ecgonine  methyl-ester  also 
appears  to  exist  in  coca,  as  also  the  corresponding  derivatives  of 
iso-cocaic  (^-truxillic)  andh  om  o-isoco  cai  c  acids. 

The  following  is  a  list  of  the  bases  hitherto  detected  in  coca 
leaves.  The  amorphous  base  to  which  Hesse  gave  the  name  of 
cocaidine  has  been  proved  to  be  a  mixture ;  and  the  volatile 
base  called  h  y  g  r  i  n  e  by  Lessen  has  not  since  been  obtained. 

CjHiyNOa,    Anhydro-ecgonine,     CgHigN  j  cQ  }  ;  or  MeCjHyN.CHiCH.COOH 

\  OH 
C9H15NO3,    Ecgonine,     .         .     CgHjaN  j  qq.OH 

CigHiyN04,  Betizoyl-ecgonine,      CgHjgNj 

C17H21NO4,  Benzoyl-ecgonine 
methyl-ester 
(cocainej, 


O.C^HjO 
CO.  OH 


r,  XT    AT  f  O.C9H7O 

Ginnamyl-ecgonine,    CgMiaiN  -!  ^^  ^^ 


C19H23NO4,   Cinnamyl-ecgonine  I  fO-CgH^O 

methyl-ester,        \  ^sHis^  j  CO.OCH3 
C3sH4eN,Os,Cocayl    -  ecgonine  >.  o.OCH3)0  )  ^   „   ^ 

methyl-ester         U  H  3N(C0.0CH  )0  i  ^^«^^*^^ 

(cocamme),  j     a    -w    \  ^' 

C40H60NA,  Homococamine,        IC8H,3N'(C0.0CH3)0  )  CicHio(CHo)«0. 
J  C8Hi3N(CO.OCH3)0  i     ''    '-^      ^^'   " 
C17H19NO2,  Benzoyl-pseudo-      I  CH^^NOCCVH^O) 
tropine,  j     o    14 

Isomerides   of   cocamine   and  homococamine  probably  exist   in 
coca,  as  Hesse  has  isolated  from  the  products  of  hydrolysis  i  s  0- 


272 


HYDROLYSIS   OF   COCA   BASES. 


c  0  c  a  i  c  and  homo-isococaic  acids.  Similarly,  Lieber- 
mann  has  isolated  two  isomers  of  cinnamic  acid,  i  s  o  c  i  n  ii  a  m  i  c 
and  allocijinamic  acids,  from  the  products  of  the  decom- 
position of  coca  bases. 

With  the  exception  of  ecgonine  and  anhydro-ecgonine,  all  the 
bodies  in  the  foregoing  list  are  saponifiable,  splitting  up  when 
heated  to  80°— 100°  with  hydrochloric  acid,  or  when  boiled  with 
alcoholic  potash,  according  to  the  following  equations : — 


2. 


3. 


4. 


a.  C17H21 


NO4 

Cocaine. 


H20  =  Ci6Hi9N04+CH,0 


'16' 
Benzoyl-ecgonine. 


Methyl 
alcohoL 


Benzoyl-ecgonine. 


H,0  =  C,H,,N03  +C,H,0, 


Ecgoiiine. 


Benzoic  acid. 


a. 


H,0 


C,8H2,NO,  +  CH,0 


Cinnamyl-ecgonine 
metliyl-ester. 


6.  C,,ll,,'SO, 


a. 


+  H20  = 

Cinnamyl-ecgonine. 

NjOg-l-SHaO 


C3SH, 


Cocamiue  (truxilline). 


h.  C2,H2<,NO,  4- 

Ecgonyl-cocaic  acid. 


H2O 


Cinnamyl- 
ecgonine. 

C,H,,N03 

Ecgonine. 

=  C,Hi,N03 

Ecgonine. 


C,H„NO, 

Ecgonine. 


Methyl 
alcohol. 

+  C8HA 

Cinnamic  acid. 

+  C27H29NOe  +  2CH40 

Ecgonyl-cocaic        Methyl 
acid.  alcohol. 

+  ^18^1604 

Cocaic  acid 
(a-truxillic  acid). 


CiyH^gOg 


+    H2O 


Benzoyl-pseudotropine. 


Pseudotropiue.     Benzoic  acid. 


From  these  equations  it  is  evident  that  the  simpler  bases  of 
coca  are  decomposition-products  of  the  natural  alkaloids  cocaine, 
cocamine,  homococaniine,  and  cinnamyl-ecgonine  methyl- ester 
(cinnamyl-cocaine),  all  of  which  readily  undergo  hydrolysis  with  for- 
mation of  ecgonine,  methyl  alcohol,  and  an  aromatic 
acid.  Benzoyl-pseudotropine  differs  from  the  other  bases  of  coca 
by  yielding  no  methyl  alcohol  on  hydrolysis. 

It  is  evident  that  the  mixed  alkaloids  of  coca  will  consist  of 
the  various  natural  bases  in  indefinite  proportion,  contaminated  by 
the  products  of  their  decomposition.  Hence  the  separation  of 
pure  cocaine  from  the  co-existing  bases  is  very  troublesome.  The 
difficulty  has  been  overcome  by  Liebermann  and  G  i  e  s  e  1 
{Ber.,  xxi.  3196)  in  an  interesting  and  ingenious  manner,  which 
allows  of  the  utilisation  of  the  valueless  and  troublesome  amorphous 
bye-products,  which  are  to  be  had  in  considerable  quantity.  The 
process  consists  in  boiling  the  mixed  bases  with  hydrochloric  acid, 
whereby  they  all  suffer  hydrolysis,  with  formation  of  ecgonine; 
and  this  base  forms  the  starting-point  for  the  subsequent  synthesis 


SYNTHESIS   OF    COCAINE.  273 

of  cocaine  by  Ein  horn's  method  (5er.,  xxi.  3335).  Thus  by- 
passing dry  hydrochloric  acid  gas  into  a  solution  of  ecgonine  hydro- 
chloride in  methyl  alcohol  until  the  solution  has  become  cold,  and 
then  boiling  the  liquid  for  an  hour  under  an  inverted  condenser, 
the  hydrochloride  of  ecgonine  methyl-ester  is  formed,  which  on 
concentrating  the  alcoholic  solution  crystallises  in  prisms,  melting 
with  decomposition  at  212°.  Cocaine  is  formed  when  this  com- 
pound is  heated  on  the  water-bath  with  an  equal  weight  of  benzoyl 
chloride  until  the  mixture  becomes  homogeneous  and  the  evolution 
of  hydrochloric  acid  ceases.  The  hot  melted  mass  is  poured  into 
water,  separated  from  the  precipitated  benzoic  acid,  and  the  cocaine 
precipitated  by  ammonia  or  an  alkaline  carbonate,  and  recrystal- 
lised  from  alcohol.  An  alternative  method  is  to  convert  the 
ecgonine  into  the  benzoyl-derivative,  and  treat  a  solution  of  the 
latter  body  in  methyl  alcohol  with  hydrochloric  acid  gas.  The 
artificial  cocaine  prepared  by  either  of  these  methods  possesses  all 
the  characters  of  the  natural  alkaloid. 

Cocaine.    Benzoyl  methyl-ecgonine.    Methyl  benzoyl-ecgonine. 
C^H^iNO,;  or  CsHtCCH,)^^  |  ^jg^^^^J^jj^ 

Cocaine  is  the  characteristic  alkaloid  of  coca  leaves,  and  has 
recently  acquired  a  place  in  the  first  rank  of  alkaloids  of  medicinal 
value.  It  may  be  extracted  from  the  plant  by  the  usual  processes, 
avoiding  as  much  as  possible  treatment  with  acids  and  alkalies,  as 
it  undergoes  hydrolysis  with  great  facility  with  formation  of  objec- 
tionable decomposition-products. 

The  synthesis  of  cocaine  was  efi'ected  by  Merck  by  treating 
together  ecgonine,  benzoic  anhydride  and  methyl  iodide  to  100°  for 
ten  hours  in  a  sealed  tube.  The  industrial  reproduction  of  cocaine 
from  ecgonine  has  been  efi'ected  and  patented  by  Liebermann 
(page  272). 

Cocaine  crystallises  from  a  strong  alcoholic  solution  in  colourless 
monoclinic  prisms,  melting  at  97°-98°  C,  and  subliming  with 
partial  decomposition  at  a  higher  temperature. 

Cocaine  is  very  slightly  soluble  in  water,^  but  dissolves  readily 
in   alcohol,   ether,  chloroform,^  benzene,   petroleum   spirit,  carbon 

^  The  solubility  of  cocaine  in  cold  water  is  probably  near  to  1  in  1300  (B.  H. 
Paul),  but  is  commonly  greatly  over-estimated,  owing  to  the  ease  with  which 
cocaine  is  decomposed  by  hot  water  with  formation  of  soluble  products, 

^  The  solubility  of  cocaine  in  chloroform  enabled  B.  H.  P  a  u  1  to  separate  it 
from  morphine,  and  prove  a  product  introduced  under  the  name  of  h  o  p  e  i  n  e, 
and  said  to  be  a  natural  narcotic  alkaloid  from  American  hops,  to  be,  in  fact,  an 
artificial  mixture  of  cocaine  and  morphine  {Pharm.  Jour. ,  [3],  xvi.  877). 
VOL.   III.   PART  II.  S 


274  CHARACTERS   OF   COCAINE. 

disulpliide  and  volatile  and  fixed  oils.  Jt  is  readily  removed  trora 
its  solutions  by  adding  ammonia  and  agitating  with  ether  or  other 
immiscible  solvent. 

An  aqueous  solution  of  cocaine  has  a  strong  alkaline  reaction  to 
litmus  and  methyl-orange,  but  does  not  affect  phenolphthalein. 
The  free  base  may  be  titrated  with  the  aid  of  either  of  the  former 
indicators.  An  aqueous  solution  of  cocaine,  if  not  very  carefully 
prepared  and  secluded  from  air,  or  preserved  by  an  antiseptic, 
mpidly  decomposes  with  formation  of  vegetable  growths. 

Cocaine  produces  on  the  tongue  a  sudden  and  characteristic 
cessation  of  feeling,  which  lasts  only  a  few  minutes.  One  drop  of 
a  4  per  cent,  solution  (of  the  hydrochloride),  if  placed  on  the 
tongue,  soon  produces  a  decided  numbness,  the  effect  being 
evanescent  unless  the  application  be  repeated.  Cocaine  also  pro- 
duces an  intense  local  anaesthetic  and  blanching  effect  on  the 
raucous  membrane.  A  single  drop  of  a  4  per  cent,  solution  suffices 
to  blanch  the  conjunctiva  of  the  eye.  Anaesthesia  of  the  eye,  of 
much  value  in  ophthalmic  operations,  can  be  produced  by  a  some- 
what larger  dose.  Dilation  of  the  pupil  is  generally  produced  by 
cocaine,  whether  applied  locally  to  the  eye  or  otherwise  introduced 
into  the  system ;  but  the  mydriasis  produced  by  cocaine  is  not  so 
invariable  and  is  far  less  intense  than  that  characteristic  of  atrojDine 
and  its  isomers. 

In  large  doses,  cocaine  has  marked  poisonous  properties.  The 
fatal  dose  for  dogs  is  from  2  to  5  grains.  The  hypodermic  injec- 
tion of  -^Q  grain  has  caused  dangerous  symptoms  in  a  girl  twelve 
years  of  age  (see  Pharm.  Jour.,  [3],  xvi.  721)/^ 

Cocaine  is  Isevo-rotatory,  the  specific  rotation  in  chloroform  solu- 
tion being  about  —  15°*8  for  the  sodium  ray;  while  the  rotation 
of  the  hydrochloride  in  dilute  alcohol  is  —  52°'2. 

Eeactions  of  Cocaine. 

Cocaine  is  precipitated  from  its  solutions  by  caustic  alkalies, 
alkaline  carbonates  and  ammonia.  It  is  almost  insoluble  in  excess 
of  ammonia,  which  is  to  be  preferred  as  a  precipitant.^  Precipitated 
cocaine  is  amorphous  when  thrown  down  from  strong  solutions,  but 
rapidly  becomes  crystalline. 

^  For  various  alarming  symptoms  produced  by  cocaine  in  dental  practice, 
see  remarks  by  Stockman  {Pharm.  Jour.,  [3],  xviii.  791).  A  resume  of 
the  pharmacology  of  cocaine  and  its  allies  appeared  in  the  Pharmaceutical 
Journal,  [3 J,  xxi.  161. 

2  If  a  solution  of  cocaine  salt  be  precipitated  with  caustic  soda  or  sodium 
carbonate,  the  filtrate  will  be  found  to  contain  a  distinct  trace  of  benzoic  acid 
resulting  from  decomposition  of  the  alkaloid  ;  but  this  is  not  the  case  if 
ammonia  be  substituted  (B.  H.  Paul). 


REACTIONS  OF  COCAINE.  275 

Mayer's  solution  precipitates  cocaine  from  extremely  dilute  solu- 
tions, and  A.  B.  Lyons  has  attempted  to  employ  the  reaction 
for  the  determination  of  cocaine,  but  with  results  which  are 
wanting  in  exactness. 

Iodised  iodide  of  potassium  gives  a  rose-coloured  precipitate 
with  a  solution  of  1  part  of  cocaine  hydrochloride  in  7,500  of 
water;  in  stronger  solutions  the  precipitate  appears  hrown,  and 
under  the  microscope  assumes  the  form  of  black  globules. 

Tannin  produces  a  distinct  cloud  in  neutral  solutions  of  cocaine 
containing  1  :  25,000,  and  a  distinct  precipitate  wdth  twice  that 
proportion.  Picric  acid  produces  in  strong  solutions  a  yellow 
precipitate,  rapidly  becoming  crystalline,  and  appearing  under  the 
microscope  in  sheaf-like  forms.  Phosphomolybdic  acid  produces 
a  faint  turbidity  in  solutions  of  1  :  50,000,  and  a  distinct  pre- 
cipitate with  1  :  12,500.  Phosphotungstic  acid  gives  a  gelatinous 
white  precipitate,  soluble  in  ammonia. 

Platinic  chloride  produces  at  once,  in  solutions  of  cocaine  hydro- 
chloride containing  1  :  400,  a  yellow  precipitate  consisting  of 
plumose  needles,  mostly  of  stellate  pattern.  In  solutions  of  1  :  600 
most  of  the  crystals  resemble  carpet-tacks,  consisting  of  short, 
well-formed  prisms,  with  a  single  branch  from  the  centre,  joined 
at  an  oblique  angle  and  tapering  to  a  point.  The  characters  of  the 
chloroplatinate  distinguish  cocaine  from  the  amorphous  base 
associated  with  it  in  coca-leaves,  the  platinum  salt  of  which  is 
far  less  soluble  in  water,  and  crystallises  in  rosette-like  forms, 
contrasting  strongly  with  the  feathery  appearance  of  the  cocaine 
salt. 

Cocaine  aurochloride  is  precipitated  on  adding  auric  chloride  to  a 
solution  of  cocaine  hydrochloride.  In  solutions  containing  1  :  3000 
an  immediate  precipitate  is  produced,  which  appears  under  the 
microscope  in  forms  resembling  fern-fronds,  generally  with  a  stellate 
arrangement.  In  solutions  of  1  :  12,000  similar  crystals  form  after 
a  short  time.  "  Cocaidine  "  aurochloride  forms  minute  prismatic 
crystals,  having  a  microscopic  appearance  quite  different  from  that  of 
the  cocaine  salt  (A.  B.  Lyons,  Amer.  Jour.  Pharm.,  Ivii.  No.  10). 

According  to  Lerch  and  Scharges,  if  a  drop  of  ferric 
chloride  be  added  to  a  solution  of  cocaine  and  the  liquid  boiled,  an 
intense  red  colour  will  be  developed  "  owing-  to  the  formation  of 
benzoic  acid."     Benzoyl-ecgonine  also  gives  the  reaction. 

Potassium  bichromate  does  not  precipitate  cocaine  except  from 
neutral  solutions,  unless  they  are  very  concentrated  (1:25);  but 
M  e  t  z  e  r  states  that  from  a  solution  containing  hydrochloric  acid, 
chromic  acid  precipitates  the  chromate,  CiyHgiNO^jH^CrO^,  in 


276  COCAINE   PERMANGANATE 

silky,  lustrous  plates  (compare  page  287).  If  0*05  gramme  of  cocaine 
hydrochloride  be  dissolved  in  5  c.c.  of  water,  and  five  drops  of  a  5  per 
cent,  aqueous  solution  of  chromic  acid  added,  each  drop  produces  a 
distinct  precipitate,  which  immediately  redissolves ;  but  if  1  c.c.  of 
strong  hydrochloric  acid  be  now  added,  a  heavy  yellow  precipitate 
of  cocaine  chromate  is  produced.  If  cocamine  be  present,  reduc- 
tion of  the  chromic  acid  will  ensue.  Ecgonine,  sparteine,  atropine, 
caffeine,  pilocarpine,  codeine  and  morphine  do  not  form  yellow 
precipitates  with  chromic  acid  or  potassium  chromate.  Quinine, 
quinidine,  cinchonine,  cinchonidine,  hydroquinine,  apomorphine, 
brucine,  strychnine  and  veratrine  form  precipitates  with  5  per 
cent,  chromic  acid  if  the  solutions  are  neutral ;  but,  according  to 
K.  Metzer  (Pliarm.  Zeit.,  xxxiv.  697),  cocaine  is  singular  in 
being  precipitated  only  after  addition  of  hydrochloric  acid. 

F.  Giesel  (Pharm.  Zeit,  1886,  page  132)  has  observed  that 
cocaine  permanganate  is  very  stable  compared  with  the  corre- 
sponding salts  of  the  majority  of  alkaloids.  Hence,  if  1  centi- 
gramme of  cocaine  hydrochloride  be  dissolved  in  one  or  two  drops 
of  water,  and  about  1  c.c.  of  a  3  per  cent,  solution  of  potassium 
permanganate  be  added,  a  purple-violet  crystalline  precipitate  of 
cocaine  permanganate  is  produced,  the  supernatant  liquid 
acquiring  a  purple-violet  tint.  A.  B.  Lyons  recommends  that  a 
strong  solution  of  the  cocaine  salt  should  be  used,  and  the  per- 
manganate employed  in  decinormal  solution  (3'162  grammes  per 
litre).  The  precipitate  is  unstable,  and  decomposes  in  a  few  hours 
even  at  the  ordinary  temperature,  leaving  a  brown  hydrated  man- 
ganese dioxide.  If  the  liquid  containing  the  precipitate  be  heated 
to  boiling  decomposition  occurs  at  once,  but  without  the  production 
of  any  peculiar  odour.  But  if  examined  under  the  microscope 
when  first  thrown  down,  the  precipitate  is  found  to  consist,  wholly 
or  in  part,  according  to  the  strength  of  the  cocaine  solution,  of 
translucent,  violet-red,  rhombic  (nearly  rectangular)  plates  of  great 
beauty,  often  grouped  together  to  form  rosettes.  A  5  per  cent, 
solution  of  cocaine  gives  a  copious  precipitate  at  once,  and  a  2  per 
cent,  solution  after  a  short  time ;  but  with  a  1  per  cent,  solution 
the  crystals  only  form  as  evaporation  takes  place. 

The  behaviour  with  potassium  permanganate  serves  to  detect 
an  admixture  of  methyl  cinnamyl-ecgonine  and  certain  other  im- 
purities in  cocaine  hydrochloride.  The  presence  of  these  causes  an 
immediate  reduction  of  the  permanganate  in  the  cold.  The  first 
drop  or  two  of  the  reagent  produces  a  brown  discoloration,  while 
the  precipitate  thrown  down  by  a  further  addition  is  more  or  less 
brown,  instead  of  a  distinct  violet-purple  or  red.  If  a  limited 
qiiantity  of  the  reagent  be  employed,  and  the  liquid  heated   to 


SALTS   OF  COCAINE.  277 

boiling,  in  presence  of  impurities  a  distinct  odour  will  be  developed 
in  some  cases  resembling  that  of  bitter-almond  oil,  and  in  others 
like  that  of  crude  cocaine  (A.  B.  Lyons,  Amer.  Journ.  Pharm., 
1886,  page  240).  The  behaviour  of  other  alkaloids  with  potassium 
permanganate  is  described  on  page  144. 

According  to  F.  da  Silva  (Compt.  Bend.,  cxi.  348;  Pharm. 
Jour.,  [3],  xxi.  162),  when  treated  by  Vitali's  test  for  atropine 
(page  257),  even  a  minute  quantity  of  cocaine  (0'0005  gramme) 
developes  a  distinct  and  peculiar  odour,  recalling  that  of  pepper- 
mint or  citronella.  No  other  alkaloid  extracted  by  benzene  from 
an  amnion iacal  solution  behaves  at  all  similarly,  though  atropine, 
hyoscyamine,  strychnine,  codeine  and  eserine  give  colour-reactions, 
and  the  last-named  alkaloid  developes  a  disagreeable  smell  resem- 
bling phenyl-carbamine  (page  46).  Delphinine,  brucine,  and  vera- 
tiine  develop  slight  odours  which  cannot  be  mistaken  for  that 
produced  by  cocaine.  A.  C.  Stark  (Pharm.  Jour.,  [3],  xxi.  848) 
has  confirmed  Da  Silva's  statements,  but  considers  the  odour  scarcely 
distinctive  enough  to  render  the  test  completely  reliable. 

Salts  of  Cocaine. 

Cocaine  Hydrochloride.  Hydrochlorate  of  Cocaine.  C^yHg^N  O^jHCl. 
This  salt,  wdiich  is  readily  prepared  by  neutralising  cocaine  by 
hydrochloric  acid,  crystallises  from  alcohol  in  short  prisms  melting 
at  181°'5.  The  crystals  from  the  aqueous  solution  contain,  according 
to  A.  B.  Lyons,  9 '6  per  cent,  of  water,  while  those  from  the 
alcoholic  solution  are  anhydrous.  The  salt  is  not  hygroscopic,  but 
is  soluble  in  less  than  its  own  weight  of  water,  forming  a  thick 
syrupy  liquid.  It  is  readily  soluble  in  spirit,  but  with  less  facility 
in  absolute  alcohol,  chloroform,  and  amylic  alcohol ;  and  is  prac- 
tically insoluble  in  ether,  petroleum  spirit,  and  fixed  and  volatile 
oils.  Ether  precipitates  cocaine  hydrochloride  from  its  solutions 
in  absolute  alcohoP  and  chloroform. 

Cocaine  Hydrohromide,  BHBr,2H20,  crystallises  readily  from 
its  aqueous  solution  in  transparent  prisms,  stable  in  the  air. 

Cocaine  Acetate  is  readily  soluble  in  water.  It  is  difficult  to 
obtain  it  in  a  crystalline  condition,  as  acetic  acid  is  given  olf  during 
the  evaporation  of  its  solution. 

Cocaine  Oleate  readily  crystallises,  and  is  soluble  in  oleic  acid 
and  fixed  oils. 

Cocaine  gives  crystalline  salts  with  sulphuric,  boric  and  oxalic 
acids.     The  citrate  is  hygroscopic,  and  crystallises  with  difficulty. 

^  Stockman  {Pharm.  Jour.,  [3],  xvii.  862)  gives  the  sohibiKty  of  pure 
cocaine  hydrochloride  in  chloroform,  absolute  alcohol,  and  amylic  alcohol  ab 
1  in  48,  1  iu  34,  and  1  in  70  respectively ;  but  B.  H.  Paul  does  not  tind  such 
large  proportions  of  solvent  necessary. 


278  COMMERCIAL   COCAINE. 

Cocaine  Benzoate,  Ci^Hg^NO^jC^HgOg'  ™'^y  be  prepared  by  mixing 
molecular  proportions  of  cocaine  and  benzoic  acid.  It  is  a  very 
soluble  salt,  obtainable  with  difficulty  in  acicular  crystals,  the 
solution  usually  drying  up  to  a  gummy  mass,  which  gradually 
acquires  a  crystalline  structure.  A  sample  of  commercial  cocaine 
benzoate  of  French  origin  was  found  by  B.  H.  Paul  to  give  no 
precipitate  of  cocaine  with  ammonia,  and  no  benzoic  acid  with 
hydrochloric  acid.  It  consisted  ofbenzoyl-ecgonine  (Pharm. 
Jour.,  [3],  xvi.  817).  According  to  A.  Bignon  (Pharm.  Jour.^ 
[3],  xvi.  721),  the  anaesthesia  produced  by  a  5  per  cent,  solution 
of  cocaine  benzoate  lasts  during  four  consecutive  hours,  and  is  not 
preceded  by  the  sensation  of  pain  produced  by  the  hydrochloride. 

Examination  of  Commercial  Cocaine  and  its  Salts. 

The  absolute  purity  of  cocaine  and  cocaine  salts  intended  for 
medicinal  use  is  essential,  as  various  undesirable  and  even 
dangerous  symptoms  are  produced  by  certain  impurities  liable  to 
be  present.^ 

Orude  Cocaine  has  for  some  time  been  manufactured  in  South 
America  for  export  to  European  markets  in  place  of  coca  leaves, 
which  have  been  found  liable  to  deterioration  in  transit.  B.  H. 
Paul  {Pharm.  Jour.,  [3],  xviii.  782)  describes  it  as  a  white  or 
yellowish  pulverulent  substance  compressed  into  thin  cakes.  It 
contains  not  only  earthy  substances,  sodium  carbonate  and  lime 
salts,  but  also  a  waxy  substance  and  traces  of  petroleum.  Its 
manufacture  has  probably  been  effected  by  extracting  the  coca 
leaves  with  petroleum  spirit,  washing  out  the  alkaloid  with  an 
acid,  and  then  precipitating  it  with  lime  or  sodium  carbonate.  It 
is  represented  as  containing  from  80  to  upwards  of  90  per  cent,  of 
alkaloid,  but  the  proportion  of  crystallisable  cocaine  present  varies 
considerably,  in  one  instance  not  exceeding  one-half  of  the  total 
alkaloid  present  (85  per  cent.).  The  remaining  portion  was  pre- 
cipitated on  adding  ammonia  to  its  solution  in  hydrochloric  acid  in 
oily  globules,  which  after  a  time  collected  at  the  bottom  of  the 
liquid  as  a  viscid  semi-transparent  layer,  which  ultimately  became 
more  or  less  crystalline.      In  all  cases  the  liquid  remained  quite 

1  The  characters  and  tests  for  cocaine  hydrochloride  given  in  the  British 
Pharmacopeia  of  1885  are  inadequate,  and  in  several  respects  grossly  in- 
accurate. In  the  first  issue,  it  was  incorrectly  described  as  readily  soluble  in 
ether,  whereas  in  fact  it  is  practically,  if  not  absolutely,  msoluble.  This 
mistake  is  corrected  in  the  reprint,  but  the  aqueous  solution  is  still  described 
as  having  a  bitter  taste,  which  is  not  a  characteristic  of  the  pure  salt,  and  is 
said  to  yield  a  white  precipitate  with  carbonate  of  ammonium,  soluble  in  excess 
of  the  reagent,  which  is  not  the  fact.  "The  aqueous  solution  dilates  the 
pupil  of  the  eye.  It  (?  the  aqueous  solution)  dissolves  without  colour  in  cold 
concentrated  acids,  but  chars  with  hot  sulphuric  acid. " 


CHARACTERS   OF   COCAINE.  279 

milky  for  a  considerable  time,  in  this  respect  presenting  a  marked 
contrast  to  the  rapid  clearing  of  the  liquid,  which  takes  place  when 
pure  cocaine  is  precipitated  from  the  solution  of  its  hydrochloride. 

The  analysis  of  a  sample  of  crude  cocaine  by  E.  R.  Squibb 
showed: — Moisture,  3'25  per  cent.;  residue  insoluble  in  ether, 
5*25;  impurity  soluble  in  ether,  050;  pure  alkaloid,  89'94  ;  and 
loss,  r06  per  cent.  {Jour.  Soc.  Cliem.  Ind.,  viii.  724,  1013). 

A  convenient  method  of  purifying  cocaine  is  to  recrystallise  it 
several  times  from  strong  alcohol,  and,  when  a  certain  degree  of 
purity  has  been  attained,  precipitate  the  base  from  its  solution  in 
10  parts  of  strong  alcohol  by  addition  of  5  measures  of  water. 

Paul  and  C  o  w  n  1  e  y  have  pointed  out  that  the  solubility  of  a 
sample  of  cocaine  in  petroleum  spirit  cannot  be  relied  on  as  a  proof 
of  its  purity,  since  cinnamyl-cocaine  behaves  similarly. 

John  Williams  {Year-Book  Pharm.,  1887,  page  502)  pro- 
posed to  purify  and  assay  commercial  cocaine  hydrochloride  by 
dissolving  it  in  the  smallest  possible  quantity  of  absolute  alcohol 
(sp.  gr.  0'795),  and  adding  to  this  solution  six  times  its  measure 
of  dry  ether,  when  the  cocaine  hydrochloride  is  precipitated  in  a 
finely-divided  but  perfectly  crystalline  condition.  Unfortunately, 
as  pointed  out  by  B.  H.  Paul,  the  hydrochlorides  of  the  amorphous 
bases  and  of  benzoyl-ecgonine  are  precipitated  under  the  same  con- 
ditions ;  and  hence  the  method  is  useless  for  the  assay  of  crude 
cocaine  hydrochloride  or  for  the  elimination  of  impurities,  though 
serviceable  for  improving  the  appearance  of  a  pure  salt  and  con- 
verting it  into  a  convenient  form  for  use.^ 

Cocaine  hydrochloride  should  be  perfectly  colourless,  and  soluble 
in  water  to  a  perfectly  colourless  solution,  which  ought  to  be  absolutely 
neutral  to  litmus-paper.  The  solution  of  the  pure  salt  keeps  fairly 
well,  but  in  presence  of  common  impurities  is  decomposed  with 
great  facility.  In  the  dry  solid  state,  cocaine  hydrochloride  under- 
goes no  change  by  keeping.  It  ought  to  be  perfectly  free  from 
odour;  but  as  sold  it  not  unfrequently  retains  the  odour  of  a 
solvent  used  in  its  preparation,  or  has  a  peculiar  butyric  or  mousy 
smell,  or  even  a  distinct  benzoic  odour.  In  any  case,  a  sample 
having  a  distinct  odour  must  be  regarded  with  suspicion. 

Pure  cocaine  hydrochloride  is  always  distinctly  crystalline,  though 
much  of  the  commercial  article  presents  an  amorphous  or  granular 
^  Paul  adds  that  it  is  a  mistake  to  attempt  the  purification  of  cocaine  hydro- 
chloride at  all.  The  free  alkaloid  is  much  more  susceptible  of  purification, 
and  may  be  obtained  in  very  fine  crystals  either  from  ether  or  alcohol.  From 
pure  cocaine  the  hydrochloride  can  be  readily  prepared,  as  the  neutral  solution 
maybe  evaporated  to  dryness  without  decomposition,  and  the  resultant  dry 
salt  can  be  readily  converted  into  a  good-looking  crystalline  condition  'by* 
Williams'  method. 


280  COCAINE   HYDKOCHLORIDE. 

appearance.  The  tendency  to  crystallise  is  so  marked  that  B.  H. 
Paul  {Pharm.  Jour.,  [3],  xviii.  781)  regards  an  amorphous  condi- 
tion, or  even  difficult  crystallisability,as  an  indication  of  the  presence 
of  impurity.  Paul  states  that  on  dissolving  5  to  10  grains  of  a 
pure  sample  in  1  drachm  of  water  and  rapidly  evaporating  the 
solution  (in  a  glass  basin)  on  a  water-bath,  the  dry  residue  obtained 
will  be  white  and  opaque,  presenting  a  radiating  crystalline  structure, 
while  in  the  case  of  an  impure  mixed  salt  the  residue  will  be  more 
or  less  yellow,  translucent,  and  of  a  gummy  or  resin  oid  character. 

The  most  definite  test  for  the  purity  of  cocaine  hydrochloride  is 
said  by  Antrich  (^Ber.,  xx.  310)  to  be  the  optical  activity.  In 
dilute  alcoholic  solution,  at  20°  C,  the  specific  rotatory  power  is 
S„=  -(52°-18  +  0-1588g),andS„=  - (67-982 -0-15827c);  where 
q  is  the  weight  of  dilute  alcohol  of  "9353  specific  gravity  at  ^  (which 
corresponds  to  a  mixture  of  6  parts  by  weight  of  absolute  alcohol 
with  9  parts  of  water)  in  100  parts  by  weight  of  the  solution, 
and  c  is  the  weight  of  hydrochloride  in  100  volumes  of  the  solu- 
tion. When  g  =  0,  or,  in  other  words,  the  solution  is  aqueous, 
S„=  -  52°-2  ;  when  q  is  100,  S„=  -  68°-06. 

The  characteristics  of  cocaine  hydrochloride  should  be,  according 
to  Beckurts,  that  it  should  give  a  clear  and  colourless  solution 
in  water ;  leave  no  residue  on  ignition ;  give  a  colourless  solution 
in  concentrated  sulphuric  acid,  when  dissolved  in  the  proportion  of 
0'020  gramme  to  1  c.c. ;  that  a  concentrated  aqueous  solution 
should  be  absolutely  neutral  (to  litmus) ;  not  immediately  reduce 
potassium  permanganate  ;  and  when  heated  with  the  latter  reagent 
give  off  no  odour  of  bitter-almond  oil. 

The  German  Pharmacopoeia  (1890)  prescribes  the  following 
tests  for  cocaine  hydrochloride  : — 0*1  gramme  is  dissolved  in  5  c.c. 
of  water,  and  3  drops  of  diluted  sulphuric  acid  added.  This  solution 
should  be  coloured  violet  by  1  drop  of  a  1  per  cent,  solution  of 
potassium  permanganate,  and  if  kept  in  a  closed  vessel  the  colora- 
tion should  but  slightly  decrease  in  half  an  hour.  One  c.c.  of 
sulphuric  or  nitric  acid  should  dissolve  O'l  gramme  of  a  cocaine  salt 
without  coloration. 

The  following  test  is  due toH.  Maclagan  {Amer.  Drug.,  1 887, 
page  22  ;  Pharm.  Jour.,  [3],  xvii.  686) : — One  grain  of  cocaine 
hydrochloride  is  dissolved  in  2  ounces  of  water,  2  drops  of  strong 
ammonia  are  added,  and  the  walls  of  the  containing  vessel  rubbed 
from  time  to  time  with  a  glass  rod ;  in  a  quarter  of  an  hour  a  good 
crop  of  glistening  crystals  separate.  When  the  cocaine  is  not 
very  pure  the  solution  remains  clear,  or  else  deposits  only  a  small 
crop.  With  a  good  sample  a  dense  precipitate  is  produced  either 
at  once  or  on  stirring,  and  soon  acquires  a  crystalline  condition, 


COMMERCIAL   COCAINE. 


281 


the  liquid  rapidly  clearing.     When  the  cocaine  contains  more  than 
4  per  cent,  of  amorphous  alkaloid  the  solution  becomes  milky. 

B.  H.  Paul  (Pharm.  Jour.,  [3],  xviii.  783)  has  pointed  out 
that  the  precipitate  of  cocaine  produced  in  Maclagan's  test  redis- 
solves  if  left  for  a  long  time  in  the  ammoniacal  solution,  owing  to 
its  conversion  into  the  soluble  base  benzoyl-ecgonine.  He  describes 
a  quantitative  application  of  the  ammonia  test  (using  a  2  per  cent. 
solution  of  the  salt)  which,  in  the  case  of  good  samples  free  from 
odour  and  colour,  will  fairly  indicate  the  purity  and  value ;  but,  in 
the  case  of  bad  samples,  regard  must  also  be  paid  to  the  character 
of  the  precipitated  alkaloid.  This  is  done  by  adding  the  ammonia 
gradually,  with  constant  stirring,  as  long  as  a  crystalline  precipitate 
forms  and  the  liquid  clears  promptly.  When  the  precipitate  begins 
to  form  clots  which  adhere  to  the  sides  of  the  beaker,  and  the 
liquid  remains  milky,  the  precijDitate  already  formed  is  separated, 
and  the  amorphous  precipitate  produced  on  further  addition  of 
ammonia  collected  separately.^  The  following  results  were  obtained 
by  B.  H.  Paul  by  the  examination  of  commercial  cocaine  hydro- 
chloride by  the  above  process  ; — 


Ammonia  Precipitate, 

per  cent. 

Sample  Number. 

Water,  per  cent. 

1 

On  Sample.              i 

=  0n  Dry  Salt. 

1 

•90 

85-6 

86-3 

2 

■50 

84-3 

84-7 

3 

84-0 

84 

4 

I'oo 

83-6 

84-00 

6 

•43 

82-6 

82^95 

6 

1-19 

81  •SS 

82^33 

7 

•43 

81-04 

81-40 

8 

9^47 

74-9 

8-2-75 

9 

2  00 

/Cryst.         66-4  > 
iAmorph.    12-2  f 

80-2 

10 

0-57 

/  Cryst.        43 -28). 
\Amorph.    31-93) 

78-66 

11 

2^93 

y  Cryst.         41-7  > 
\Amorph.    31-7  f 

75-5 

12 

... 

65-3 

... 

The  ammonia  precipitates  from  the  first  eight  of  these  samples  were 
perfectly  crystalline,  without  any  trace  of  stickiness ;  they  deposited 
rapidly,  and  left  the  supernatant  liquid  quite  clear  and  bright.  In 
the  case  of  samples  9,  10  and  11,  a  considerable  proportion  of  the 
alkaloid  was  of  an  amorphous  sticky  nature,  quite  different  from 
that  obtained  from  a  pure  salt.  No.  12  was  so  impure  that  it 
was  impossible  to  effect  a  fractional  precipitation  quantitatively. 

^The  amorphous  alkaloid  when  freed  from  colouring  matter  is  a  clear 
yellowish  transparent  substance,  resembling  thick  Canada- balsam,  and  the 
hydrochloride  forms  a  varnish-liku  mass  that  cannot  be  reduced  to  powder. 


BENZOYL-ECGONINE. 

Paul  states  that  the  principal  impurity  iu  the  last  four  samples 
was  undoubtedly  the  hydrochloride  of  the  amorphous  alkaloid 
associated  with  cocaine  in  coca  leaves  (see  page  287),  the  salts 
having  been  probably  produced  by  evaporating  the  solution  of  the 
mixed  bases  in  hydrochloric  acid  ;  and  it  is  questionable  whether 
the  presence  of  this  amorphous  base  should  be  tolerated  in  a  pro- 
duct which  purports  to  be  "  cocaine  hydrochloride." 

Decomposition-Products  of  Cocaine. 

Benzoyl-ecgonine.  CieHjgNO^;  or  C8Hi3N(O.CyH50).CO.Oa 
This  base  may  be  prepared  by  the  action  of  benzoic  anhydride 
or  benzoic  chloride  on  ecgonine,  and  is  also  a  product  of  the  action 
of  acids  or  water  on  cocaine.  Hence  it  occurs  as  a  bye-product  of 
the  manufacture  of  cocaine.^  On  a  large  scale,  benzoyl-ecgonine  is 
prepared  by  gradually  adding  a  little  more  than  one  molecule  of 
benzoic  anhydride  to  a  hot  saturated  aqueous  solution  of  one 
molecule  of  ecgonine,  and  heating  the  mixture  on  the  water-bath 
for  about  an  hour.  After  cooling,  the  product  is  shaken  with  ether 
to  remove  unchanged  benzoic  anhydride  and  acid,  and  the  residual 
benzoyl-ecgonine  washed  with  a  little  water  to  dissolve  unaltered 
ecgonine.  The  yield  is  about  80  per  cent,  of  the  ecgonine 
employed,  and  an  additional  quantity  can  be  obtained  by  concen- 
trating the  mother-liquor  and  again  treating  it  witli  benzoic 
anhydride. 

Benzoyl-ecgonine  crystallises  with  4H2O  in  transparent,  flat, 
trimetric  prisms,  resembling  ammonium  oxalate,  which  melt 
at  a  variable  temperature  ranging  from  87°-140°.  When  fusion 
occurs  at  the  lower  temperature  (as  happens  when  the  heat  is 
rapidly  applied),  the  substance  resolidifies  on  further  heating,  and 
melts  again  at  195°,  turning  brown  at  the  same  time. 

Benzoyl-ecgonine  is  sparingly  soluble  in  cold  water,  but  readily 
in  hot  water,  alcohol,  and  dilute  alkalies  and  acids.  It  is  almost 
insoluble  in  ether. 

The  acetate  and  sulphate  of  benzoyl-ecgonine  crystallise  in 
prisms.  BHAuCl^  forms  small,  yellow,  anhydrous  scales,  soluble 
in  alcohol  but  only  sparingly  so  in  water. 

When  heated  with  alkalies  or  with  hydrochloric  acid  to  100°  in 
sealed  tubes,  the  base  is  decomposed  into  benzoic  acid  and 
ecgonine.  By  treatment  with  methyl  iodide  it  yields  cocaine. 

1  Benzoyl-ecgonine  is  easily  produced  by  heating  cocaine  with  about  20 
parts  of  water  in  a  closed  tube.  The  cocaine  melts  at  about  90°,  but  gradually 
dissolves  on  maintaining  the  temperature  at  100°.  The  change  is  facilitated 
by  agitation,  and  in  about  twelve  hours  a  clear  solution  is  obtained,  which  is 
only  faintly  acid  if  pure  cocaine  was  employed. 


ECGONINE.  283 

Benzoyl-ecgonine  does  not  appear  to  have  much,  if  any,  anaes- 
thetic effect  when  applied  to  the  eye,  and  exerts  only  a  moderate 
dilating  action  on  the  pupil.  R.  Stockman  states  that  it  is 
very  irritating  to  the  mucous  membranes,  and  vrhen  injected  sub- 
cutaneously  produces  tetanic  spasms.  In  many  respects  its  action 
resembles  that  of  caffeine,  but  paralysis  of  the  sensory  nerves  is 
quite  absent  (Pharm.  Jour.,  [3],  xvi.  898). 

EcGONixXE.  CgHigJN'Og ;  or  C8Hi3N(OH).COOH.  (See  also  page 
270.)  Ecgonine  is  obtained,  together  with  benzoic  acid  and  methyl 
alcohol,  by  heating  cocaine  with  concentrated  liydrochloric  acid  to 
100°  in  sealed  tubes  (page  272).^  Also,  when  cocaine  or  its 
hydrochloride  is  heated  with  20  parts  of  water  and  10  of  baryta  to 
120°  in  sealed  tubes,  it  is  decomposed  according  to  the  equation  : — 

C17H21NO4  +  2H2O  =  C^HgOg  +  CgHi.NOg  +  CH,0 
The  actual  products  are  methyl  alcohol,  barium  benzoate,  and  a  com- 
pound of  barium  benzoate  with  the  barium  compound  of  ecgonine, 
(2B8i{CgH^^'NO^\4-Ba{OBz\-\-xK^OX  which  forms  slender  pris- 
matic needles,  very  soluble  in  water  and  alcohol,  but  only  slightly 
soluble  in  ether.  This  compound  is  a  convenient  source  of 
ecgonine.  On  subjecting  it  to  dry  distillation  it  yields  an 
isatr opine,  the  chloroplatinate  of  which  forms  bulky,  orange- 
red,  deliquescent  crystals  containing  (C8Hj5NO)2H2PtClg. 

Ecgonine  crystallises  from  absolute  alcohol  in  monoclinic  prisms 
containing  1  aqua,  which  melt  at  198°;  or,  after  drying  at  140° 
to  expel  the  water  of  crystallisation,  at  205°.  Ecgonine  is  very 
soluble  in  water,  sparingly  in  absolute  alcohol,  and  insoluble  in 
ether.     It  has  a  slight  bitter-sweet  taste. 

When  ecgonine  is  heated  with  moderately  strong  sulphuric 
acid,  neither  carbonic  oxide  nor  formic  acid  is  formed,  but  a  base 
is  produced  which  bears  the  same  relation  to  ecgonine  that  ether 
bears  to  alcohol.     It  unites  both  with  acids  and  bases. 

C.  E.  Merck  (Ber.,  xix.  3002)  states  that  ecgonine,  when 
distilled  with  nearly  dry  barium  hydroxide,  yields  methylamine 
and  not  ethylamine  as  one  of  the  products,  thus  agreeing  with  the 
behaviour  of  tropine  when  similarly  treated. 

When  ecgonine  (or  anhydro-ecgonine)  is  oxidised  with  potas- 
sium permanganate,  or  nitric  acid,  succinic  acid  is  formed  (E  i  n- 

^  Liebermann  and  Giesel  obtain  ecgonine  on  a  lar^e  scale  by  boiling  the 
amorphous  base  obtained  in  the  manufacture  of  cocaine  for  about  an  hour  with 
hydrochloric  acid.  The  filtered  solution  is  evaporated  to  dryness,  the  residue 
treated  with  a  little  alcohol  to  remove  impurities,  and  the  residual  ecgonine 
hydrochloride  decomposed  by  sodium  carbonate,  the  liberated  base  being 
recrystallised  from  alcohol. 


284  BASES  ALLIED  TO  COCAINE. 

horn,  Ber.,  xxi.  47),  a  fact  which  shows  tliat  the  side-chain  in 
the  molecule  of  ecgonine  must  be  either  in  the  a-  or  /3-position. 

Ecgonine  contains  a  carboxyl-group,  and  hence  behaves  at  once 
as  an  acid  and  a  base.  It  has  a  neutral  reaction,  but  reacts  with 
alkalies  to  form  gummy  compounds  of  faint  alkaline  reaction, 
■which  crystallise  with  difficulty  and  are  very  soluble  in  water  and 
alcohol.  Ecgonine  liydrocJdoride,  CgHjgNOgjHCl,  forms  triclinic 
tables,  difficultly  soluble  in  alcohol  and  melting  at  246°  C. 
B^HgPtCle,  after  drying  at  140°,  melts  at  226°.  It  is  extremely 
soluble  in  water,  and  is  deposited  in  orange-red  prisms  on  adding 
excess  of  alcohol  to  its  aqueous  solution.  BHAuCl^  is  a  greenish 
yellow,  gummy  substance,  very  soluble  in  water  and  alcohol. 

"With  iodised  potassium  iodide,  ecgonine  yields  a  reddish  brown 
precipitate,  rapidly  changing  to  reddish  yellow,  microscopic  tables 
or  prisms.  In  dilute  solutions  the  precipitate  is  formed  only  after 
concentration.  In  the  animal  system,  cocaine  is  converted  into 
ecgonine,  which  may  be  detected  in  the  urine  by  this  test. 

Anhydro-ecgonine.  C9H13XO2;  or  CgNH^Me.CHiCH.COOH. 
This  base  is  formed  by  the  action  of  phosphorus  oxy chloride  or 
pentachloride  on  ecgonine,  or  by  heating  cocaine  for  eight  hours  to 
140°  with  glacial  acetic  acid  which  has  been  saturated  with  hydro- 
chloric acid  gas.  It  forms  colourless  crystals  melting  at  235", 
soluble  in  water  and  alcohol,  but  insoluble  in  ether,  chloroform, 
benzene  and  petroleum  spirit.^  When  anhydro-ecgonine  is  heated 
with  water  to  150°,  methylamine  is  liberated.  It  combines 
directly  with  bromine  to  form  a  base  containing  CgHjgBrgNOg, 
the  hydrochloride  of  which  melts  at  184°.  The  salts  of  anhydro- 
ecgonine  are  crystallisable.  BHCl  crystallises  from  absolute  alcohol 
in  white  needles  melting  at  240°-241°. 

Bases  allied  to  Cocaine. 

Dextro-cocaine.  CiyHgiNO^.  Einhorn  and  Marquardt 
{Ber.,  xxiii.  469,  979)  have  found  that  by  warming  with  aqueous 
potash  for  twenty -four  hours,  ecgonine  is  converted  into  a  base 
which  differs  from  ordinary  ecgonine  in  being  much  less  soluble  in 
absolute  alcohol,  and  having  a  much  higher  melting-point  (254°)  ; 
but  especially  in  being  dextro-rotatory. 

From  this  dextro -ecgonine  a  synthetic  dextro-cocaine  may  be 
prepared  as  a  colourless  oil,  which  solidifies  on  standing,  and  is 
readily  soluble  in  ether,  alcohol,  benzene,  and  petroleum  spirit. 

Dextro-cocaine  may  be  obtained  in  crystals,  melting  at  43°-46°, 

^  Hence  it  is  best  isolated  by  treating  the  solution  of  its  hydrochloride  with 
argentic  oxide  (compare  page  20).  It  may  be  purified  by  precipitation  from 
its  alcoholic  solution  by  ether. 


BASES  ALLIED  TO  COCAINE.  285 

by  treating  its  solution  with  a  crystal  of  benzoyl-dextroecgonine 
ethyl- ester. 

The  salts  of  dextro-cocaine  crystallise  well.  BHCl  is  much  more 
difficultly  soluble  than  the  hydrochloride  of  ordinary  cocaine,  and 
melts  at  205°  instead  of  181°'5.  BHNO3  is  especially  characteristic. 
100  parts  of  water  at  20°  C.  dissolve  1'55  parts  of  the  nitrate, 
which  is  precipitated  in  crystals  on  adding  nitric  acid  to  solutions 
of  other  salts  of  the  base.  This  behaviour  distinguishes  dextro- 
cocaine  from  ordinary  cocaine.  BgHgPtClg  crystallises  from  hot 
water  in  yellowish  needles.  BHAuCl^  crystallises  from  dilute 
alcohol  in  needles  melting  at  148°. 

Dextro-cocaine  was  found  to  resemble  ordinary  cocaine  in  its 
physiological  effects,  except  that  local  ansesthetic  action  commenced 
more  rapidly,  and  disappeared  in  a  shorter  time. 

With  chromic  acid,  potassium  permanganate,  and  auric  chloride, 
dextro-cocaine  behaves  like  cocaine. 

CocETHYLiNE,  HoMococAiNB,  or  Beuzoyl-ecgonine  ethyl-ester, 
CjgHggXO^,  is  the  higher  homologue  of  cocaine,  which  base  it 
closely  resembles.  It  is  prepared  by  heating  benzoyl-ecgonine  with 
ethyl  iodide  and  alcohol  for  eight  hours  at  100°.  It  crystallises 
from  alcohol  in  vitreous  prisms  melting  at  108°-109°,  and  is  also 
soluble  in  ether  but  nearly  insoluble  in  water.  The  cliloroplatinate 
forms  bright  yellow,  rhombic  plates,  resembling  the  cocaine  salt 
but  more  crystalline.  Physiologically,  homococaine  is  similar  in  its 
effects  to  cocaine,  but  is  weaker  and  less  toxic,  and  does  not  appear 
to  be  mydriatic. 

The  higher  homologues  of  cocethyline,  containing  propyl  and 
isobutyl  groups,  have  been  prepared  by  similar  means;  and 
also  by  passing  hydrochloric  acid  gas  into  a  solution  of  benzoyl- 
ecgonine  in  the  corresponding  alcohol, 

CiNNAMYL-cocAiNE.  CjgHggNO^ ;  or  C9Hi3(CH3)(C9H70)N03 . 
This  base  has  been  obtained  synthetically  by  passing  dry  hydro- 
chloric gas  into  a  solution  of  cinnamyl-ecgonine  (prepared  by  heat- 
ing ecgonine  with  cinnamic  anhydride  and  water).  It  forms  large 
colourless  crystals  melting  at  121°,  and  is  almost  insoluble  in  water, 
but  readily  soluble  in  alcohol,  ether,  &c.  When  boiled  with 
hydrochloric  acid  it  is  decomposed  readily  and  quantitatively  into 
cinnamic  acid,  ecgonine,  and  methyl  alcohol.  BHCl  is  precipitated 
as  an  oil  which  solidifies  after  a  time  on  adding  a  large  volume 
of  ether  to  a  strong  acidulated  solution  of  the  salt  in  alcohol. 
BgHgPtClg  crystallises  in  microscopic  needles  melting  at  217^. 
When  treated  with  a  cold  solution  of  potassium  permanganate 
cinnamyl-cocaine  and  its  salts  immediately  evolve  a  strong  odour 
of  benzaldehyde  (bitter-almond  oil). 


286  COCAMINE. 

Cinnamyl-cocaine  has  been  proved  to  occur  naturally  in  coca 
leaves  from  various  sources.  Paul  and  C  o  w  n  1  e  y  (Pharm. 
Jour.^  [3],  XX.  165)  examined  a  sample  of  leaves  containing  1*75 
per  cent,  of  total  alkaloid,  nearly  0*5  per  cent,  being  crystallisable 
from  petroleum  spirit,  but  which,  nevertheless,  contained  very  little 
real  cocaine.  On  oxidation  by  permanganate  the  crystallisable 
alkaloid  yielded  abundance  of  benzaldehyde,  and  in  other  respects 
corresponded  with  cinnamyl-cocaine  (methyl  cinnamyl-ecgonine). 

CocAMiNE.  a-Truxilline.  C38H4gN20g+H20.  This  base  is  con- 
tained in  notable  quantity  in  Truxillo  coca  leaves.  Hesse  found  0*6 
per  cent,  in  leaves  of  a  different  kind,  and  states  that  East  Indian 
coca  leaves,  and  especially  those  from  Java,  contain  cocamine  in  con- 
siderable amount.  Liebermann  regards  cocamine  as  identical  with 
the  base  originally  described  by  him  asy-isatropyl  cocaine, 
and  afterwards  asa-truxilline;  but  Hesse  contends  that  Lieber- 
mann's  product  was  a  mixture,  of  which  cocamine  was  a  leading 
constituent.^ 

Cocamine  has  a  bitter  taste.  Hesse  and  Stockman  found  its 
physiological  effect  to  be  similar  to  that  of  cocaine,  but  somewhat 
weaker,  and  its  anaesthetic  action  especially  weak.  On  the  other 
hand,  G.  Falkson  alludes  to  y-isatropylcocaine  (cocamine)  as  a 
"  deadly  alkaloid,"  and  Liebermann  describes  it  as  a  heart-poison 
which  does  not  produce  anaesthesia.  To  its  presence  as  an 
impurity,  the  occasionally  highly  toxic  effects  of  commercial  cocaine 
are  not  improbably  due. 

Cocamine  is  precipitated  by  caustic  alkalies  and  ammonia  from 
solutions  of  its  salts,  and  after  exposure  at  the  ordinary  tempera- 
ture in  a  desiccator  retains  one  molecule  of  water.  It  is  readily 
soluble  in  alcohol,  ether,  benzene  and  chloroform,  but  differs  from 
cocaine  in  being  very  sparingly  soluble  in  petroleum  spirit.  Neither 
the  free  base  nor  its  salts  have  been  obtained  crystallised.  Repeated 
solution  in  hydrochloric  acid  and  reprecipitation  by  soda  was  the 
process  employed  by  Liebermann  to  purify  the  cocamine  from  the 
co-occurring  isococamine  (/8-truxilline),  which  is  also  bitter,  and 
produces  numbness  of  the  tongue  very  slowly  by  reason  of  its 
sparing  solubility. 

Both  cocamine  and  its  isomeride  have  been  obtained  syntheti- 
cally. When  hydrolysed  by  mineral  acids  they  yield  ecgonine, 
methyl  alcohol,  and  cocaic  and  isococaic  acids  respectively. 

Cocaic  Acid,  CgHgOg,  or  C^gH^gO^,  called  by  Liebermann  y-isa- 
tropic  acid  or  a-truxillic  acid,  is  produced  by   boiling 

^  The  composition  of  cocamine  and  its  allies  has  formed  the  subject  of  an 
embittered  controversy  between  Liebermann  and  Hesse  {PJutrm.  Jour.,  [3],  xxi. 
1109,  11'29;  xxii.  61,  101). 


BENZOYL- PSEUDOTRO  PINE.  287 

cocamiiie  with  hydrochloric  acid.  The  isomeric  isococaic  acid 
(^-isatropic  or  /5-truxillic  acid)  is  the  similar  product  from  iso- 
cocamine.  Cocaic  acid  melts  at  274°,  is  tasteless  and  odourless, 
insoluble  in  water,  and  nearly  insoluble  in  ether,  from  which, 
however,  it  crystallises  in  forms  resembling  benzoic  acid.  Isococaic 
(/3-truxillic)  acid  melts  at  206°.  Both  cocaic  and  isococaic  acids 
yield  cinnamic  acid  and  other  products  on  distillation. 

Benzoyl-pseudotropine,  CgH^^NO-CyHgO,  is  a  base  isolated  by 
G  i  e  s  e  1  from  a  narrow-leaved  coca  plant  cultivated  in  Java  [Ber.j 
xxiv.  2336).  It  somewhat  resem])les  dextrococaine,  but  is  opti- 
cally inactive,  and  differs  from  other  coca-bases  in  not  yielding 
methyl  alcohol  on  hydrolysis ;  for,  when  heated  with  hydrochloric 
acid  under  a  reflux  condenser  for  some  hours,  it  is  completely 
decomposed  into  benzoic  acid  and  pseudotropine, 
CgHjgNO  (see  page  247).  In  this  respect  the  base  resembles 
atropine  and  the  other  tropeines.^  Benzoyl-pseudotropine  is 
obtained  as  a  milky  precipitate  which  does  not  become  crystalline 
on  adding  sodium  carbonate  to  the  solution  of  one  of  its  salts. 
The  base  may  be  extracted  by  ether,  and  on  evaporating  the 
solution  is  obtained  as  an  oil  which,  when  quite  dry,  solidifies 
in  radiating  crystals  melting  at  49°  C.  It  has  a  strong  alkaline 
reaction,  and  is  easily  soluble  in  alcohol,  ether,  chloroform,  benzene 
and  petroleum  spirit.  BHCl,  obtained  by  passing  hydrochloric 
acid  gas  into  an  ethereal  solution  of  the  base,  crystallises  in  white 
needles  melting  at  271°.  The  solution  gives  a  bulky  crystalline 
precipitate  with  mercuric  chloride.  BgHgPtClg  is  a  flesh-coloured 
precipitate,  insoluble  in  hot  water,  alcohol  and  ether.  BHAuCl^ 
crystallises  from  water  in  sparingly  soluble  yellow  needles,  melting 
at  208°.  The  picrate  forms  fine  yellow  needles,  difficultly  soluble 
in  water.  With  potassium  bichromate,  benzoyl-pseudotropine 
yields  a  crystalline  precipitate,  instead  of  an  oily  one  like  cocaine 
and  dextrococaine. 

Amorphous  Bases  of  Coca. 

In  isolating  cocaine  there  is  found  in  the  mother-liquors  a 
variable  quantity  of  a  basic  substance  commonly  known  as 
"amorphous  cocaine,"  while  the  names  cocaicine  and 
cocainoidine  have  also  been  applied  to  it.  Amorphous  cocaine 
is  described  by  K  Stockman  {Pharm.  Jour.,  [3],  xvii.  861)  as 
ranging  in  colour  from  dark  yellow  to  dark  brown,  and  consistence 
from  that  of  treacle  to  a  sticky  tenacious  solid,  having  a  peculiar 

^  Liebreich  finds  that  benzoyl-pseudotropine  introduced  into  the  eyes  of 
rabbits  occasions  strong  local  ansesthesia  and  a  slight  enlargement  of  the  pupil, 
in  this  respect  acting  more  like  cocaine  than  atropine. 


288  AMORPHOUS   BASES   OF   COCA. 

smell  resembling  that  of  nicotine,  and  a  bitter  and  aromatic  taste. 
Stockman  concludes  that  "amorphous  cocaine"  is  in  reality  a 
solution  of  ordinary  crystalline  cocaine  in  h  y  g  r  i  n  e,  the  liquid 
alkaloid  said  to  have  been  found  in  coca  leaves  by  Lassen. 
The  amorphous  alkaloid  is  extracted  from  the  coca  in  greater  or 
less  amount  by  the  processes  now  employed  by  manufacturers, 
and  its  presence  is  considered  by  Stockman  to  account  for  certain 
disagreeable  effects  resulting  from  the  employment  of  cocaine  con- 
taining the  impurity.  Thus  if  the  hydrochloride  of  the  impure 
alkaloid  be  used  to  produce  anaesthesia  of  the  conjunctiva  con- 
siderable irritation  ensues. 

W.  C.  Howard  {Pharm.  Jour.^  [3],  xviii.  71)  to  a  certain 
extent  agrees  with  Stockman's  view  as  to  the  nature  of  amorphous 
cocaine.  He  found  that  when  the  solution  of  the  bases  of  coca 
in  hydrochloric  acid  was  completely  precipitated  with  platinic 
chloride,  and  the  liquid  filtered  after  standing  over-night,  the 
mixed  platinum  salts  obtained  were  amorphous  or  semi-crystalline, 
and  somewhat  light  in  colour.  When  the  precipitate  was  washed 
with  a  large  quantity  of  water  at  a  temperature  not  exceeding 
80°  C,  the  cocaine  chloroplatinate  dissolved,  and  the  alkaloid  could 
be  obtained  therefrom  in  a  crystalline  state.  The  fraction  of  the 
platinum  salt  insoluble  in  water  when  decomposed  by  sulphuretted 
hydrogen,  and  extracted  with  ammonia  and  ether,  left  on  evapo- 
rating the  ether  a  liquid  base  which  thickened  considerably  on 
keeping,  but  in  which  no  crystals  appeared  even  after  a  week. 
It  had  an  intensely  bitter  taste,  formed  an  uncrystallisable 
hydrochloride,  and  a  chloroplatinate  containing  18'5  per  cent,  of 
platinum  (against  19'3  per  cent,  in  the  cocaine  salt)^  and  not 
affected  by  hot  water,  all  which  characters  distinguish  the  base 
from  the  description  of  h  y  g  r  i  n  e  given  by  L  o  s  s  e  n  {Annal. 
der  Pharm.,  cxxi.  374). 

0.  Hesse  states  that  when  working  on  the  bases  from  the 
broad-leaved  coca,  separating  the  cocaine  as  hydrochlorate  "by 
a  special  process,"  and  ascertaining  the  absence  of  cocamine,  the 
residual  mixture  was  dissolved  in  dilute  hydrochloric  acid  and  the 
solution  treated  with  ammonia  in  excess,  this  process  of  solution 
and  reprecipitation  being  repeated  until  the  precipitate  dissolved  in 
hydrochloric  acid  gave  a  solution  which  showed  no  fluorescence  on 
dilution  with  water,  thus  proving  its  freedom  from  hygrine. 
The  precipitate,  after  being  further  washed  with  water  at  80°  C, 
gave  a  melted  mass  which  was  spread  on  glass  plates  and  dried  at 

^  Hesse  {Pharm.  Jour.^  [3],  xviii.  71,  437)  considers  that  Howard's 
platinum  salt  was  liydrated,  being  in  reality  the  chloroplatinate  of  an  amor- 
phous base  isomeric  with  cocaine. 


HYGRINE.  289 

60°,  by  which  means  it  was  obtained  in  transparent,  brittle,  hygro- 
scopic laminae  which  were  nearly  insoluble  in  water  and  alkaline 
liquids,  but  dissolved  readily  in  alcohol,  ether,  chloroform,  benzene 
and  petroleum  .spirit.  The  solution  was  alkaline  to  litmus,  but 
without  effect  on  phenolphthalein  {Pharm.  Jour.^  [3],  xviii.  71, 
437).  When  boiled  with  alcoholic  baryta,  or  heated  in  a  sealed 
tube  with  hydrochloric  acid,  the  amorphous  base  yields  benzoic 
acid,  and  another  product  not  yet  identified. 

From  a  later  investigation  {ihid.,x\x.  867),  Hesse  concludes  that 
the  amorphous  bases  from  true  coca  consist  chiefly  of  benzoyl  com- 
pounds of  an  oily  non-volatile  base,  together  with  some  cocamine; 
while,  on  the  contrary,  those  obtained  from  Truxillo  leaves  consist 
essentially  of  cocamine,  and  the  cinnamyl  compounds  of  the  before- 
mentioned  oily  base  ;  and  the  cocamine  is  in  each  case  accompanied 
by  a  base  containing  Hg  less  than  cocamine. 

A  specimen  of  the  amorphous  base  from  coca  examined  by  B. 
H.  Paul  {Pharm.  Jour.^  xviii.  784)  is  described  by  him  as  being 
pale  yellow,  and  of  the  consistence  of  thick  Canada  balsam.  It 
had  a  faint  odour  at  once  suggestive  of  benzoin  and  butyric  acid, 
and  a  distinctly  bitter  taste,  but  produced  no  anaesthetic  effect  on 
the  tongue  until  after  the  lapse  of  some  minutes,  and  then  very 
slight  compared  with  that  produced  by  cocaine. 

Hygrine.  Under  this  name  several  bases  have  been  described, 
which  were  either  impure  or  actually  dissimilar.  The  name  was 
first  applied  byLossen  to  a  liquid  volatile  base  which  has  not 
since  been  obtained.  The  hygrine  of  0.  Hesse  {Pharm.  Jour., 
[3],  xviii.  438)  is  best  prepared  from  the  mother-liquor  obtained 
in  the  preparation  of  "  cocaidine  "  from  amorphous  cocaine.  This 
is  treated  with  caustic  soda  and  ether,  the  ethereal  solution 
separated  and  evaporated,  and  the  residue  distilled  with  water. 
The  hygrine  passes  into  the  distillate,  which  is  faintly  acidified  by 
hydrochloric  acid,  evaporated  to  dryness,  and  the  residue  treated 
with  caustic  soda  and  ether.  The  ether  leaves  on  evaporation  a 
brown  oily  residue,  which,  on  treatment  with  dilute  acetic  acid, 
deposits  a  brown  smeary  mass,  which  is  filtered  off,  the  solution 
again  treated  with  caustic  soda  and  ether,  and  the  ether  evapo- 
rated. 

Hygrine  thus  obtained  is  a  yellowish  oily  substance  having  an 
odour  suggestive  of  that  of  quinoline.  It  has  a  slight  burning  taste, 
and  a  strong  alkaline  reaction  on  litmus,  but  does  not  alter  phenol- 
phthalein. It  is  but  little  soluble  in  water  or  solution  of  caustic 
soda,  but  dissolves  readily  in  alcohol,  ether  and  chloroform. 
Hygrine  volatilises  with  steam,  and  at  a  higher  temperature  may 
be  distilled  alone. 

VOL.  III.  PART  II.  T 


290  HYGRINE. 

BHCl  is  crystallisable.  Its  dilute  aqueous  solution  exhibits 
a  marked  fluorescence,  not  perceptible  in  a  concentrated  solution, 
and  destroyed  by  sodium  chloride  and  other  substances.  An 
aqueous  solution  of  hygrine  hydrochloride  becomes  milky  on 
addition  of  caustic  soda,  owing  to  the  separation  of  the  free  base 
in  minute  oily  globules,  which  aggregate  after  a  time.  Hesse 
attributes  to  hygrine  the  formula  C]L2^i3-^  ^^^  ^^®  constitution  of 
a  trimethylquinoline,  but  Liebermann  regards  it  as  a 
mixture  of  oxygenated  bases,  which  may  be  separated  by  fractional 
distillation.  The  most  volatile  boils  at  193°— 195°,  and  has  the 
formula  CgHigNO,  but  is  not  identical  with  tropine  (page  246). 
The  less  volatile  portion  of  hygrine  appears  to  contain  C-^^Bi^^N^^, 
and  cannot  be  distilled  unchanged  at  the  ordinary  pressure.  Neither 
of  these  bases  is  affected  by  heating  to  120°  with  concentrated 
hydrochloric  acid  (Ber.,  xxii.  675). 

Hesse  points  out  that  hygrine  probably  does  not  pre-exist  in 
coca  leaves,  but  is  a  product  of  decomposition.  He  states  that 
when  sound  coca  leaves  are  moistened  with  ammonia,  shaken  with 
ether,  and  the  ether  treated  with  dilute  hydrochloric  acid,  the  acid 
liquid  on  dilution  at  first  shows  no  fluorescence,  but  after  a  time 
exhibits  this  character  distinctly. 

R.  Stockman  {Pharm.  Jour.,  [3],  xviii.  701)  states  that 
hygrine  exists  in  coca  leaves  in  very  minute  quantity  only,  and  some 
manufacturers  never  meet  with  it.  He  found  it  in  cocaine  mother- 
liquors  given  him  by  Messrs  Howard  &  Sons,  and  notably  in  the 
alcoholic  tincture  of  freah  coca  leaves.  Stockman  finds  hygrine 
to  distil  very  imperfectly  with  steam  in  presence  of  cocaine.^ 
The  whole  of  the  statements  respecting  hygrine  require  con- 
firmation. 

Stockman  describes  hygrine  as  a  brown  oily  liquid  with  a  char- 
acteristic smell.  A  drop  placed  on  the  tongue  causes  a  burning 
sensation.  Frogs  were  killed  by  the  subcutaneous  injection  of 
hygrine  mixed  with  water.  There  was  considerable  irritation  at 
the  place  of  injection,  while  the  muscles  all  over  the  body,  the 
bowels,  and  the  serous  membranes  were  studded  with  numerous 
minute  haemorrhages. 

Coca  Leaves. 

The  coca  leaves  occurring  in  commerce  are  chiefly  of  two  kinds, 

^  The  treatment  is  stated  to  have  decomposed  the  cocaine  present,  some 
benzoic  acid  passing  over  with  the  hygrine.  It  seems  probable  that  a  difficultly 
volatile  or  non-volatile  benzoate  of  hygrine  was  formed.  A  better  result  would 
probably  have  been  obtained  by  adding  an  alkali  to  the  contents  of  the 
retort. 


COCA    LEAVES.  291 

the  one  being  obtained  from  Erytliroxylon  coca}  which  was  the 
original  trade-product,  and  the  other,  which  is  of  more  recent 
importation,  derived  from  Jamaica  and  St  Lucia.  Coca  leaves 
contain,  in  addition  to  the  ordinary  plant-constituents  and  the 
characteristic  alkaloids,  cocatannic  acid. 

CooATANNic  Acid  (C.  J.  H.  Warden,  Pharm.  Jour.,  [3], 
xviii.  985)  has  the  probable  composition  Cj^H^gOg.  It  forms  a 
sulphur-yellow  powder,  which  appears  under  the  microscope  in 
filiform  crystals  interlaced  in  masses.  It  melts  at  189°-191°  to  a 
deep  red  liquid,  and  is  only  slightly  soluble  in  cold  water,  cold 
absolute  alcohol,  ether  and  chloroform.  In  hot  water  it  dissolves 
more  readily,  and  rather  freely  in  boiling  absolute  alcohol.  A  hot 
aqueous  solution  of  cocatannic  acid  has  an  acid  reaction.  It  yields 
no  reaction  with  ferrous  salts  (according  to  some  observers,  green), 
but  with  ferric  gives  a  dark  green  coloration,  and  reduces  silver 
nitrate  slowly  in  the  cold  and  immediately  on  heating,  but  not 
Fehling's  solution.  It  does  not  precipitate  gelatin.  The  alco- 
holic solution  gives,  with  alcoholic  lead  acetate,  a  precipitate 
varying  from  yellow  to  orange-red.  When  heated  with  hydro- 
chloric acid  to  100°,  cocatannic  acid  yields  a  glucose  and  a 
phlobaphene.  The  products  of  potash-fusion  do  not  appear  to  be 
characteristic.  They  are  said  to  include  butyric  and  traces  of 
benzoic  acid. 

C.  J.  H.  Warden  (Phami.  Jour.,  [3],  xviii.  1010,  1027)  has 
observed  that  coca  leaves  which  are  rich  in  cocatannic  acid  also 
contain  much  alkaloid,  and  suggests,  with  much  probability,  that 
the  cocaine  and  allied  alkaloids  of  coca  leaves  exist  in  combina- 
tion with  cocatannic  acid.  Warden,  in  nine  specimens  of  the  dry 
leaves  from  plants  grown  in  different  parts  of  India,  found  from 
6'36  to  12'64  per  cent,  of  ash  (average  8*85  per  cent.),  and  from 
0-358  to  1-671  per  cent,  of  "crude  alkaloid"  (average  0-982  per 
cent.).  Warden  did  not  succeed  in  obtaining  a  crystalline  alkaloid 
from  Indian  coca,  but  does  not  consider  the  non-crystalline  character 
detracts  from  its  physiological  activity  Q). 

A.  G.  Howard  (Pharm.  Jour.,  [3],  xix.  569)  has  published 
analyses  of  a  large  number  of  coca  leaves  from  different  sources. 
His  results  show  that  while  Erythroxylon  coca  yields  about  f  per 
cent,  of  alkaloid,  the  proportion  obtainable  from  most  other  species 
of  Erythroxylon  is  extremely  insignificant,  and  in  some  cases  the 
alkaloid  is  wholly  absent.  In  Brazil  alone  there  are  upwards  of 
eighty  species  of  Erythroxylon. 

^  The  coca  plant  is  a  small  shrub  from  4  to  6  feet  in  height,  growing  and 
largely  cultivated  in  Peru  and  Bolivia,  and,  to  some  extent,  in  Brazil  and  the 
Argentine  Republic. 


292  COCA   LEAVES. 

H.  T.  Pf  eif  f  er  (Ohem.  Zeit,  xi.  783,  818;  Jour.  Soc.  Cliem. 
Ind.j  vi.  561)  has  described  the  following  process  of  manufactur- 
ing crude  cocaine  hydrochloride  direct  from  coca  leaves : — The 
disintegrated  leaves  are  digested  in  closed  vessels  at  70°  C,  for 
two  hours,  with  a  very  weak  solution  of  caustic  soda  and  petroleum 
boiling  between  200°-250°.  The  mass  is  filtered,  pressed  while 
still  tepid,  and  the  filtrate  allowed  to  stand  until  the  petroleum 
has  completely  separated  from  the  aqueous  liquid.  The  former 
is  then  drawn  off  and  carefully  neutralised  with  very  weak 
hydrochloric  acid,  when  a  bulky,  white  precipitate  of  cocaine 
hydrochloride  is  obtained,  together  with  an  aqueous  liquid  from 
which  a  further  quantity  of  the  salt  can  be  recovered  by 
evaporation. 

The  dried  product  contains  about  75  per  cent,  of  real  alkaloid, 
besides  traces  of  "  hygrine,"  gum,  and  other  matters.  A  repetition 
of  the  process  proved  that  the  whole  of  the  alkaloid  was  removed 
by  a  single  treatment.  The  soda  cannot  be  substituted  by  lime, 
nor  the  hydrochloric  acid  by  other  acid. 

Assay  of  Coca  Leaves.  Pfeiffer  employs  a  similar  process  for 
the  assay  of  coca  leaves,  100  grammes  of  which  should  be  digested 
in  a  flask  with  400  c.c.  of  water,  60  c.c.  of  10  per  cent,  soda 
solution,  and  250  c.c.  of  petroleum.  The  mixture  is  kept  warm 
for  some  hours  and  shaken  occasionally,  then  strained,  the  residue 
pressed,  and  the  filtrate  allowed  to  separate.  The  aqueous  liquid 
is  tapped  off,  and  the  oily  layer  titrated  with  ^  hydrochloric 
acid.  The  number  of  c.c.  required,  multiplied  by  0042,  gives  the 
percentage  of  cocaine  in  the  sample.  The  fresh  leaves  contain 
from  0'3  to  0'6  per  cent.,  but  this  proportion  decreases  considerably 
if  the  leaves  have  been  stored  for  any  length  of  time  before  being 
worked  up. 

For  the  assay  of  coca,  v.  d.  Marck  (Jour.  Pliarm.,  [5],  xx.  500; 
Analyst,  xiv.  115),  after  a  trial  of  various  processes,  recommends 
that  50  grammes  of  the  leaves  should  be  mixed  with  20  grammes 
of  calcined  magnesia  and  moistened  with  a  little  water,  dried  at 
60°,  and  the  mixture  exhausted  with  ether.  The  ether  is  distilled 
off,  and  the  residue  treated  with  30  c.c.  of  2  per  cent,  hydrochloric 
acid.  The  solution  is  filtered,  and  repeatedly  shaken  with  ether  to 
remove  colouring-matters.  Ammonia  is  then  added,  and  the 
cocaine  extracted  by  shaking  three  times  with  25  c.c.  of 
ether.  After  standing  for  a  short  time  over  some  fragments  of 
calcium  chloride,  the  ether  is  evaporated,  and  the  residual  alkaloid 
weighed. 

For  the  estimation  of  the  cocaine  in  coca  leaves,  A.  B.  Lyons 
{Jour.    Pharm.t    [5],  xiii.    197)    recommends    that    the    finely- 


ASSAY   OF   COCA    LEAVES.  293 

powdered  leaves  should  be  macerated  for  twenty-four  hours  with 
eight  times  their  weight  of  a  mixture  of  95  volumes  of  ether  with 
5  of  ammonia.  From  an  aliquot  part  of  this  liquid  the  alkaloid 
is  extracted  by  agitation  with  acidulated  water,  the  ether  separated, 
and  the  alkaloid  liberated  from  the  aqueous  liquid  by  means  of 
ammonia  and  again  extracted  with  ether,  which  is  then  evaporated 
to  dryness  and  the  cocaine  weighed.  The  associated  bases,  being 
soluble  in  water  and  insoluble  in  ether,  remain  in  the  ammoniacal 
liquid.  Lyons  states  that  coca  leaves  do  not  contain  more  than 
0"8  per  cent,  of  cocaine,  and  sometimes  the  proportion  is  as  low  as 
0'15  per  cent.  The  leaves  rapidly  deteriorate  in  value,  so  that  in 
six  months  they  are  practically  worthless.  The  product  from 
deteriorated  leaves  is  always  more  or  less  coloured,  and  very  little 
of  it  is  crystallisable ;  while  that  from  good  leaves  is  almost 
colourless,  and  easily  crystallises. 

M.  Bignon  (Lima)^  states  that  coca  leaves  dried  in  damp 
weather,  with  frequent  turning,  and  sheltered  from  dew  and 
moisture,  yield  easily  0*8  per  cent,  of  alkaloid,  and  the  finer  sorts 
can  give  I'O  per  cent,  and  upwards  under  exceptional  circum- 
stances. Coca  leaves  dried  in  damp  weather,  or  pressed  into 
sacks  before  being  completely  dried,  undergo  a  gradual  f«rment 
which  ends  in  the  complete  destruction  of  the  cocaine. 


OPIUM  ALKALOIDS. 

Opium,  the  nature  and  characters  of  which  are  described  at 
length  on  page  332,  is  remarkable  for  the  large  number  of  nitro- 
genised  organic  principles  contained  in  it.  At  least  nineteen 
alkaloids  have  been  isolated  from  opium,  and  the  list  is  probably 
still  incomplete.  Most  of  these  bodies  have  well-defined  basic  pro- 
perties, and  the  majority  are  poisonous.  Some  of  them,  as  mor- 
phine and  narcotine,  occur  in  opium  in  considerable  quantity,  but 
the  greater  number  are  present  in  very  small  proportion,  and  are 
entirely  absent  from  some  samples. 

The  following  table  exhibits  the  leading  characters  of  the  nitro- 
genised  principles  which  have  been  recognised  in  opium.  In  some 
cases  the  basic  character  is  very  feebly  marked,  while  certain  of 
the  alkaloids  {e.g.,  pseudomorphine,  oxynarcotine)  are  probably 
decomposition-products. 

^ Pharm.  Jour.,  [3],  xvi.  267;  xvii.  606.  Bignon  states  that  the  Indian 
never  chews  coca  leaves  alone  ;  but  mixes  them  with  ashes  and  lime,  whereby 
the  alkaloid  is  liberated,  and  thus  obtains  the  anaesthetic  properties  and 
numbing  effect  upon  the  mucous  membrane  of  the  stomach  which  he  desires. 


294 


OPIUM   BASES. 


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SAXGUINARINE.  295 

In  addition  to  the  alkaloids  in  the  above  list,  deuteropine, 
opionine,  papaverosine,  and  porphyroxine  (page 
330)  have  been  described,  but  their  existence  as  individuals  is 
very  doubtful. 

"With  one  or  two  exceptions,  the  alkaloids  of  opium  are  strictly 
peculiar  to  Papaver  somniferum ;  while,  on  the  other  hand,  the 
poisonous  alkaloid  sanguinarine,  which  is  present  in  aU  other 
papaveraceous  plants,  does  not  appear  to  exist  in  Papaver.^ 
Indeed,  with  the  exception  of  pro t opine,  which  is  probably 
identical  with  the  interesting  alkaloid  macleyine,  CgoHigNOg, 
obtained  by  Eykman  (Tear-jBooA;  Pharm.,    1882,   p.   33)  from 

^  Sangtjinarine,  C17H15NO4,  is  best  prepared  from  the  root  of  Sanguinaria 
Canadensis  (Year-Book  Pharm.,  1871,  310  ;  1875,  256  ;  1879,  201).  The  root 
is  exhausted  with  water  acidulated  with  acetic  acid,  the  solution  precipitated 
by  ammonia,  the  precipitate  dried  and  exhausted  with  ether,  and  the  ethereal 
solution  treated  with  hydrochloric  acid  gas,  which  throws  down  the  hydro- 
chloride of  sanguinarine  (RHCl  +  HgO)  as  a  scarlet  precipitate,  which  may  be 
purified  by  solution  in  hot  water  and  repetition  of  the  treatment  with  ammonia, 
ether,  &c.  The  free  alkaloid  melts  at  160°,  and  crystallises  from  hot  alcohol 
in  small  white  needles  having  an  acrid,  burning  taste.  Sanguinarine  is  a 
powerful  narcotic  poison  ;  the  powder  causes  sneezing.  It  is  insoluble  in  water, 
but  soluble  in  ether,  chloroform,  amylic  alcohol,  benzene  and  petroleum  spirit. 
The  solutions  exhibit  a  strong  violet  fluorescence  without  absorption-bands, 
and  are  optically  inactive.  The  salts  of  sanguinarine  are  orange-red,  and 
hence  the  free  alkaloid  is  reddened  by  the  fumes  of  hydrochloric  acid.  The 
precipitation  of  the  bright  red  hydrochloride  from  the  ethereal  solution  of 
the  alkaloid,  as  above  described,  is  a  highly  characteristic  reaction.  Alcoholic 
sulphuric  acid  behaves  similarly.  Aqueous  solutions  of  sanguinarine  salts 
exhibit  a  violet  fluorescence,  and  are  precipitated  white  by  ammonia  and  bright 
red  by  potassio-iodide  of  mercury.  BaHgPtClg  +  HgO  forms  a  bright  orange 
precipitate,  very  slightly  soluble  in  water. 

Chelerythrinr,  which  occurs  inchelidonium  and  several  other  plants, 
is  regarded  by  Schiel  as  identical  with  sanguinarine,  but  E.  Schmidt  agrees 
with  Naschold  that  the  more  probable  formula  is  C19H17NO4. 

Chelidonine,  C20H19NO5  +  HgO,  is  the  principal  alkaloid  of  the  twelve 
said  to  exist  in  the  root  of  the  common  celandine  {C'helidonium  majus),  and 
occurs  in  several  other  plants  in  association  with  sanguinarine  or  chelerythrine 
(or  both).  Chelidonine  forms  colourless  monoclinic  crystals  melting  at  130°, 
soluble  in  alcohol,  but  insoluble  in  water  and  but  slightly  soluble  in  ether. 
The  salts  of  chelidonine  are  colourless,  and  have  a  very  acrid  and  bitter  taste. 
The  hydrochloride  forms  fine  crystals  which  require  fully  300  parts  of  cold 
water  for  solution,  which  character  may  be  used  for  isolating  the  alkaloid. 
Chelidonine  is  a  tertiary  base,  and  contains  no  methoxyl-group.  With  sugar 
and  sulphuric  acid  it  gives  a  violet  coloration.  (See  E.  Schmidt,  Pharm. 
Zeit,  1889,  58.) 

Several  other  alkaloids  besides  those  already  named  have  been  detected  in 
Chelidoniv/m  majus,  among  them  being    a-   and  /3-homocheliHonine, 


296  OPIUM   BASES. 

Macleya  cordata  (a  poisonous  Japanese  plant),  none  of  the  nitro- 
genised  substances  found  in  opium  appear  to  be  identical  with 
any  of  those  extracted  from  other  plants  of  the  family.^ 

Constitution  of  Opium  Bases. 

Some  of  the  opium  bases  are  isomeric,  while  others  are  homo- 
logous, or  else  differ  from  each  other  by  the  increments  C2H2,  CO, 
Hg,  HO,  or  multiples  of  these. 

The  tendency  to  combine  with  each  other  to  form  stable  crystal- 
line compounds,  which  renders  bhe  isolation  and  study  of  the 
cinchona  bases  so  difficult  (see  Homoquinine),  does  not  seem  to 
exist  in  the  case  of  the  opium  alkaloids. 

The  chemical  constitution  of  the  opium  alkaloids  is  not  yet 
thoroughly  understood,  but  they  have  been  proved  to  be  derivatives 
of  quinoline,  and  in  some  cases  further  advances  have  recently  been 
made. 

Morphine  (compare  page  167)  has  been  proved  by  the  researches 
of  Wright,  Grimaux,  Hesse,  Skraup,  Knorr,  and  others 
to  contain  two  hydroxy  1-groups,  one  of  which  has  a  phenolic  and 
the  other  an  alcoholic  function.  The  first  of  these  can  be  readily 
replaced  by  alkyl  and  acid  radicals,  forming  codeine,  acetylmorphine, 
&c.  The  second  hydroxyl-group  may  also  be  replaced,^  with  forma- 
tion of  bodies  of  the  type  of  methocodeine,^  which  differs  from 
thebaine  by  Hg,  thus  : — 

Morphine,  .  .  C,7Hj7(OH)NO.OH 

Codeine,  .  .  Ci7Hi7(OH)NO.OCH3 

Methocodeine,  .  .  Ci7Hi7(OCH3)NO.OCH35 

Thebaine,  .  .  Ci7Hi5(OCH3)NO.OCH3 

Ci9Hi5(OCH3)2N03,  and  (probably)  protopine  (F.  Selle,  Arch.  Pharm., 
ccxxviii.  441).  Stylophorine,  the  alkaloid  of  Stylophoron  diphyllum, 
is  apparently  identical  with  chelidonine.  Clielerythrine  is  stated  to  exist 
in  the  root  of  the  yellow  sea-poppy,  Glaucewm  luteum,  together  with 
glaucine  and  glaucopicrine,  both  of  which  form  crystallisable  salts 
(Pro bat,  Annal  d.  Chemie,  xxxi.  241).  Porphyroxine  (a  body  distinct 
from  Merck's  alleged  opium  base)  and  p  u  c  c  i  n  e  are  said  to  exist  in  san- 
guinaria  root ;  and  two  alkaloids  have  been  found  in  Eschscholtzia  Californica^ 
one  of  which  is  probably  methyl-chelidonine.  The  alleged  presence  of  morphine 
has  not  been  confirmed.  Of  all  these  bases,  only  sanguinarine  and  chelido- 
nine have  been  fairly  well  studied  ;  while  the  data  respecting  the  others  do 
not  suffice  to  characterise  them. 

^  A  base  identical  with,  or  similar  to,  narcotine  was  isolated  by  T.  and 
H.  Smith  from  the  fresh  juice  of  the  roots  of  Aconitum  Napellus^  but  other 
observers  have  not  confirmed  this  result. 

2  See  footnote  ^  on  next  page. 

^  It  is  not  certain  that  methocodeine  has  the  constitution  ascribed  to  it  in 


CONSTITUTION   OF  MORPHINE.  ^97 

The  poisonous  characters  of  morphine,  which  are  both  narcotic 
and  tetanic,  are  shared  qualitatively  by  derivatives  in  which  only 
the  hydrogen  of  the  hydroxyl  is  replaced,  as  in  codeine,  ethyl- 
morphine,  amyl-morphine,  mono-  and  di-acetyl-morphine,  benzoyl- 
morphine^  and  morphinyl-sulphonic  acid.  But  when  further  substi- 
tution takes  place,  as  in  chlorocodeine  and  methocodeine  (page  324), 
the  product  is  not  merely  a  nerve-poison,  but  a  muscle-poison. 
Apomorphine,  the  constitution  of  which  is  probably  not 
simply  that  of  an  anhydromorphine,  is  a  muscle-poison  analogous 
to  methocodeine.2 

L.  Knorr  {Berichte,  xxii.  181,  1113)  considers  that  morphine 
contains  a  reduced  phenanthrene-nucleus  and  a  methyl-group 
united  with  the  nitrogen,  and  represents  it  by  the  following 
formula : — 

OH 


/        **CH       I  Cflg 

rr       I 

CH» 


\  CH      I 


k 


It  remains  undecided  whether  the  alcohol-hydroxyl  is  connected  with 
carbon  atom  *  or  **■. 


Skraup  and  Wiegmann  (Monatsh.,  x.  110)  have  shown 
that  this  formula  requires  modification ;  for  on  heating  morphine 
to  a  high  temperature  with  alcoholic  potash,  aphenoloid  body 
and  ethyl-methylamine  are  formed,  which  fact  proves  that 

the  text.  It  is  not  improbable  that  the  alcoholic  hydroxyl  remains  intact, 
the  second  methyl-group  being  introduced  into  the  body  of  the  morphine 
molecule,  thus  :— Ci7Hi6(CH3)NO(OH).OCH3. 

^  By  heating  anhydrous  morphine  to  100°-110°  with  excess  of  benzoic 
chloride  a  dibenzoyl-derivative  is  obtained,  and  diacetylmorphine  may  be 
obtained  in  a  similar  manner.  These  compounds  were  first  obtained  by 
C.  R.  Alder  Wright  {Jour.  Chem.  Soc.,xxyu.  i.631).  When  two  acetyl- 
groups  have  been  introduced  into  morphine  no  further  substitution  can  be 
elfected — a  fact  which  confirms  the  view  that  the  morphine  molecule  contains 
only  two  hydroxyl-groups  (see  Danckwortt,  Arch.  Pharm. ,  ccxxviii. 
672). 

2  When  treated  with  excess  of  acetyl  chloride,  apomorphine  yields  only  a 
monoacetyl-derivative.  Hence,  probably,  only  one  (the  phenylic)  hydroxyl 
atom  exists  in  apomorphine,  the  second  (alcoholic)  having  been  eliminated 
during  its  formation  from  morphine. 


298  CONSTITUTION   OF  OPIUM   BASES. 

in  morphine  both  an  ethyl  and  a  methyl  group  are  directly  united 
to  the  nitrogen  atom. 

Pseudomorphine  was  formerly  represented  by  the  formula 
CiyH^^gNO^.  Hesse  found  that  the  base  contained  a  molecule  of 
water  which,  when  driven  off,  was  recovered  very  rapidly.  He 
therefore  preferred  the  formula  Ci^^Hj^NOg ;  but  more  recently  has 
abandoned  this  for  Ci7Hj^8N03,  or  preferably  Cg^HggNgOg,  the  base 
having  the  constitution  of  an  oxydimorphine.^  On  the  other  hand, 
M.  P.  Cazeneuve  {Compt.  Rend.,  1891,  p.  805)  has  obtained  a 
violet  colouring  matter  of  definite  composition  by  acting  on 
morphine  with  paranitroso-dimethylaniline  (page  75).  This  dye 
appears  to  be  an  i  n  d  a  m  i  n  e,  analogous  in  constitution  to  Bind- 
schedler's  green;  whereas,  if  pseudomorphine  were  derived  from  two 
molecules  of  morphine,  the  colouring  matter  would  have  contained 
two  morphine  residues,  and  had  the  constitution  ofasafranine 
(Part  I.  page  252).  Combination  is  not  effected  by  means  of  the 
hydroxyl-group  having  a  phenolic  function,  since  codeine  yields  a 
similar  dye. 

Narcotine,  CggHggNOy,  contains  three  methyl-groups  (besides  that 
connected  with  the  nitrogen),  the  first  two  of  which  may  be  suc- 
cessively removed  by  heating  the  alkaloid  with  strong  hydrochloric 
acid,  while  by  heating  with  fuming  hydriodic  acid  the  third  group 
may  be  removed,  nornarcotine,  CigH^yNOy,  being  produced 
together  with  methyliodide. 

When  narcotine  is  heated  with  water  under  pressure  at  150°, 
it  is  split  up  in  the  first  place  with  formation  of  opianic  acid 
and  hydrocotarnine  (page  325) : — 

The  two  products  subsequently  react  more  or  less  completely  to 
form  m e c 0 n i n  and  cotarnine,  thus  : — 

CioHi„0,+Ci2Hi,N03  =  Ci„Hj„0,+Cj2H,3N03+H20 

(compare  page  161). 

Opianic  acid,  C^^^qO^  (compare  page  203),  forms  delicate  whit© 
crystals.  It  is  reduced  to  meconin  (page  335)  by  nascent  hydro- 
gen, and  by  oxidation  with  dilute  chromic  acid  mixture  yields 
hemipinic  acid,  G-i^ifi^.  By  the  action  of  soda-lime,  opianic 
acid  yields    methyl-vanillin,   CgHj^Og,  which  when  boiled 

^  On  heating  pseudomorphine  with  acetyl  chloride,  a  tetracetyl-derivative 
is  produced ;  a  fact  which  indicates  that  the  four  hydroxyl-groups  are  still 
intact,  and  that  the  hydrogen  atoms  lost  in  the  formation  from  morphine  must 
have  been  united  with  carbon. 


CONSTITUTION   OF  NARCOTINE. 


299 


with  hydrochloric  acid  gives  vanillin,  CgHgOg  (Part  I.  page  62  ; 
see  also  Dott,  Pharm.  Jour.,  [3],  xiv.  641).^ 

Cotarnine,  CjgHjgNOg,  is  contained  in  the  mother-liquor  from 
which  the  meconin  has  crystallised.  It  forms  a  very  soluble, 
yellow,  bitter  substance.  It  is  a  fairly  strong  base,  soluble  in 
ammonia  and  fusible  in  boiling  water.  When  gently  heated  with 
very  dilute  nitric  acid  it  yields  methylamine  nitrate  and 
cotarnic  acid,  a  bibasic  acid  containing  G^.^-^^^^. 

W.  Eoser  {Annalen,  ccliv.  334,  359),  from  a  careful  considera- 
tion of  the  evidence,  considers  narcotine  to  contain  the  residues  of 
opianic  acid  and  hydrocotarnine,  and  expresses  it  by  the  following 
graphic  formula.  It  is  closely  related  to  pajpaveriney  both  being 
derivatives  of  a  benzyl-isoquinoline. 


0CH3 

A 


OCHo 


00 


OCHs 


OCH3 


HO 


CH3)N 


CH2 


O-CF2 


OCH3 


CH2         H 

Narcotine. 


CH3 


Papaverine. 


OCHs 


OCHa 


W.  Roser  {Annalen,  ccxlvii.  167)  has  obtained  an  isomer  of 
narceine  by  treating  narcotine  methochloride  in  aqueous  solution 
with  caustic  soda,  when  narcotine  methyl-hydroxide  is  precipi- 
tated. On  exposure  to  steam  this  changes  into  a  base  which  is 
possibly  identical  with  narceine,  apparently  in  accordance  with 
the  equation  :— C22H23lSr07,CH30H  +  3H20 
or  perhaps  the  new  base  is  an  anhydro-narceine 
taining  C^fi^^l^O^ZRJd. 

Narceine  has  been  expressed  by  the  constitutional  formula 

fCO.OH 


C23H29NO„2H20 ; 
con- 


(Ci3H2„N04).CO.CeH2^  O.CH3 
LO.CH, 


CgH^ 


rO.CHa 
O.CH, 


'2]  CO.  OH 
Leo.  OH 
Henaipinic  acid. 


rO.CHg 
0.CH3 
CO.H 

ICO.OH 
Opianic  acid. 


C«H 


p„  I0.CH3 

^6^2  1  CO.H 

IH 
Methyl-vanillin. 


fO.CHg 

p  TT    1  O.CH 

W^2i  CO 

ICH 

Meconin. 


.}« 


300  OPIUM  ALKALOIDS. 

General  Characters  of  Opium  Bases. 

Morphine,  codeine,  thebaine,  papaverine,  narcotine  and  narceine 
are  the  most  important  of  the  alkaloids  of  opium.  The  opium 
alkaloids  form  a  group  of  which  all  the  members  exert  a  more  or 
less  narcotic  and  tetanising  action,  but  in  very  varying  degree. 
Thus  morphine  is  almost  purely  narcotic  and  thebaine  almost 
purely  tetanising  in  its  action.^  Morphine,  codeine  and  thebaine 
have  strongly-marked  basic  characters.  They  are  strongly 
alkaline  to  litmus,  and  afford  stable  salts.^  Papaverine,  narcotine 
and  narceine,  on  the  contrary,  are  very  weak  bases  (compare 
page  305). 

The  free  alkaloids  of  opium  are  generally  but  slightly  soluble  in 
water,  but  dissolve  more  readily  in  alcohol.  In  many  instances 
the  solutions  of  the  free  alkaloids  are  strongly  alkaline  to  litmus. 
On  the  other  hand,  certain  of  them  {e.g.,  morphine,  narceine, 
laudanine)  exhibit  a  distinct  phenoloid  character,  and  form  definite 
compounds  with  the  alkahes.  The  different  behaviour  of  the 
opium  bases  to  solvents  affords  a  valuable  means  of  distinguishing 
and  separating  them.  They  are  precipitated  from  concentrated  solu- 
tions of  their  salts  by  caustic  alkalies  and  alkaline  carbonates, 
some  of  the  precipitates  dissolving  in  excess  of  the  reagent.  Most 
of  the  opium  alkaloids  (except  papaverine  and  laudanosine)  have  a 
IsBVO-rotatory  action  on  polarised  light,  but  the  specific  rotatory 
power  varies  so  greatly  with  the  solvent  and  the  concentration  of 
the  solution  that  the  fact  has  a  very  limited  practical  value. 
Many  of  the  opium  alkaloids  furnish  characteristic  colour-reactions 
when  treated  with  strong  acids  and  oxidising  agents,  which,  with 
observations  of  their  melting-points,  crystalline  form,  and  behaviour 
with  solvents,  will  suffice  for  the  recognition  of  most  of  them  when 
in  an  unmixed  state.  Their  separation  is  described  on  page  305 
et  seq. 

Behaviour  of  Opium  Bases  with  Solvents. 
The  following  table  shows  the  recorded  behaviour  of  the  opium 
bases  with  solvents.  The  figures  are  the  number  of  parts  of  the 
solvent  required  for  the  solution  of  one  part  of  the  alkaloid.  Apomor- 
phine  is  not  a  natural  constituent  of  opium,  but  is  formed  by  the 
dehydration  of  morphine,  and  introduced  into  the  table  for  con- 
venience of  comparison.  The  figures  are  the  number  of  parts  of 
the  solvent  required  for  the  solution  of  1  part  of  alkaloid. 

^  Thebaine  appears  to  be  the  most  poisonous  of  the  leading  alkaloids  of 
opium.  Papaverine  appears  to  possess  only  very  slight  poisonous  properties, 
if  any. 

^  Codeine  is  distinctly  more  strongly  basic  than  morphine,  and  a  method  of 
determining  the  former  alkaloid  has  been  based  on  the  fact  (page  323). 


SOLUBILITIES   OF  OPIUM   BASES. 


301 


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COLOUR-KEACTIONS   OF   OPIUM   BASES.  303 

The  solubility  of  opium  bases,  as  of  other  substances,  is  much 
affected  by  the  physical  condition  of  the  alkaloids,  and  to  some 
extent  by  the  manner  of  making  the  experiment. 

Colour-Reactions  op  Opium  Bases. 

Several  of  the  opium  bases  react  in  a  more  or  less  characteristic 
manner  with  potassium  permanganate  (see  page  144). 

Many  of  the  opium  alkaloids  give  brilliant,  and  in  some  cases 
characteristic,  colour-reactions  with  mineral  acids,  with  or  without 
the  aid  of  heat  and  the  addition  of  oxidising  agents.  The  colours 
obtained  vary  somewhat  with  the  mode  of  applying  the  test  and 
with  the  oxidiser  employed.  The  colours  obtained  are  modified 
in  a  marked  manner  by  very  slight  traces  of  oxidising  agents  in 
the  sulphuric  acid  used,  and  hence  this  reagent  should  be  scrupu- 
lously free  from  iron  and  oxides  of  nitrogen.  E.  K  a  u  d  e  r  re- 
commends that  the  purity  of  the  sulphuric  acid  should  be  tested 
by  codeine,  which  should  give  no  colour  even  on  heating,  while 
in  presence  of  the  faintest  trace  of  iron,  such  as  may  be  taken  up 
from  long  keeping  in  a  bottle  of  common  glass,  a  violet  coloration 
is  produced. 

The  colour-reactions  of  the  opium  alkaloids  are  best  observed  in 
the  manner  described  in  detail  on  page  3 1 3  e^  seq. 

Many  of  the  colour-reactions  of  the  opium  bases  defy 
classification,  and  such  of  these  as  appear  of  value  are  de- 
scribed under  the  alkaloids  to  which  they  refer;  but  the 
table  on  page  302  shows  many  of  the  better-known  reactions  of 
the  more  important  opium  bases,  according  to  the  most  reliable 
observers. 

If  a  trace  of  narceine  be  evaporated  with  dilute  sulphuric  acid 
at  100°  C.  a  beautiful  violet-red  coloration  appears  as  soon  as  the 
liquid  is  sufficiently  concentrated ;  changing  to  cherry-red  by  con- 
tinued heating.  After  cooling,  the  addition  of  a  trace  of  nitric 
acid  or  a  nitrite  produces  bluish  violet  streaks  in  the  red  liquid. 
The  test,  which  is  due  to  Plugge  {Jour.  Chem.  Soc,  lii.  870), 
is  said  to  be  very  dehcate  and  characteristic.  With  traces  of 
morphine,  codeine,  or  papaverine  the  liquid  remains  quite 
colourless;  with  larger  quantities  of  either  of  the  two  former 
bases  a  faint  rose-red  tint  is  obtained,  with  thebaine  a  greenish 
yellow  to  brown  colour,  and  with  narcotine  a  red  to  reddish 
brown. 

According  to  Serena  (Analyst,  x.  149),  the  following  colour- 
reactions  are  produced  on  treating  certain  of  the  opium  alkaloids 
successively  with  a  few  drops  of  concentrated  sulphuric  acid  and  a 
very  small  quantity  of  a  dilute  solution  of  ferric  chloride,  with  the 
aid  of  slight  heat. 


304 


COLOUR-REACTIONS   OF  OPIUM   BASES.     ' 


Alkaloid. 

With  Sulphuric  Acid. 

On  adding  Ferric  Chloride. 

Apomorphine, 

Codeine,   . 
Papaverine, 
Opionine, . 
Narceine, . 
Codamine, 

Not  changed. 

light  violet-red,  deepened 
by  heat  (compare  p.  322). 
Purplish  red. 

No  coloration. 

Coflfee-brown. 

Violet  streaks  at  point  of 
contact,  the  bluish  green 
mass  becoming  light  violet 
on  heating. 

Sky-blue. 

Colourless ;       on     heating, 

violet. 
Green ;   rapidly     becoming 

deep-blue. 
Bluish  green. 

Green-blue  ;  at  100",  violet. 

The  following  table  shows  the  colour-reactions  observed  by  He  s  s  e 
(Jour.  Cliem.  Soc,  xxiv.  1064)  when  certain  of  the  opium  bases 
are  treated  with  pure  concentrated  sulphuric  acid,  and  with  acid 
containing  traces  of  oxide  of  iron  or  oxides  of  nitrogen.  The 
reactions  with  ferric  chloride  are  also  shown. 


Alkaloid. 

With^mre  Sulphuric  Acid. 

With  Acid  containing 
Oxide  of  Iron. 

With  Feme 
Chloride. 

At  20*  C. 

At  150"  C. 

At  20°  C. 

At  150°  C. 

Codeine,     . 
Codamine,  . 
Lanthopine, 
Laudanine, . 

Laudanosine, 

Protoplne,  . 

Cryptopine, 

Hydrocotar- 
nine. 

Colourless. 

Colourless. 

Colourless. 

Very        faint 
rose-red. 

Faint  rose-red. 

Yellow,  chang- 
ing to  red  and 
bluish  red 

Yellow,  chang- 
ing to  violet.2 

Yellow. 

Dirty  green.i 

Dirty  red- 
violet. 

Brownish  yel- 
low. 

Deep  red- 
violet. 

Deep         red- 
violet. 

Dirty     green- 
ish brown. 

Dirty  green. 

Crimson  -  red, 
changing  to 
dirty      red- 
violet. 

Blue. 

Intense  green- 
blue. 

.. 

Intense     rose 
colour. 

Brownish  -  red 
(resembling 
cobalt     ni- 
trate    solu- 
tion). 

Deep  violet. 

Deep  violet. 

Dirty  green. 
Deep  violet. 

Green,  chang- 
ing to  deep 
violet. 

Green,  chang- 
ing to  deep 
violet. 

Dirty     green- 
ish brown. 

Dirty  green. 

Dirty        red- 
violet. 

No  reaction. 
Dark  green. 
No  reactions. 
Emerald-green.2 

No  reaction. 

No  reaction. 
No  reaction. 

^  According  to  E.  Kauder  {Pharm.  Jour.,  [3],  xviii.  250),  if  the  sulphuric 
acid  be  quite  pure  no  coloration  is  yielded  with  codeine  even  on  heating,  but 
a  blue  colour  is  produced  if  traces  of  iron  be  present.  Cryptopine  dissolves 
with  violet  colour,  changing  to  deep  blue,  and  fading  to  greenish  on  standing 
or  heating  to  150°.  In  presence  of  oxide  of  iron,  cryptopine  is  said  to  dissolve 
in  sulphuric  acid  with  deep  violet-rose  colour,  changing  to  violet  and  deep 
blue,  and  becoming  greenish  on  heating  to  150°.  The  hydrochloride  gives  a 
yellow  coloration  when  first  treated  with  acid. 

2  According  to  Merck,  laudanine  gives  a  violet  colour  with  ferric  chloride. 


COLOUR-REACTIONS   OF  OPIUM  BASES.  305 

Hesse  employs  the  colour-reactions  of  the  opium  bases  -with  pure 
sulphuric  acid  as  a  means  of  grouping  them,  thus  : — 


Coloration  at  150'. 

Alkaloids. 

Dirty  dark  green. 

Dirty  red-violet. 

Dirty  green  to  green-brown. 

Dark  violet  or  blue. 

Black-brown  to  dark  brown. 

Codeine,  morphine,  pseudomorphine. 

Codamine,   laudanine,     laudanosine,    narcotine, 

hydrocotamine. 
Tliebaine,  cryptopine,  protopine. 

Papaverine.! 

Narceine,  lanthopine. 

With  acid  containing  iron,  codamine,*  laudanine  and  laudanosine 
are  stated  to  give  a  dark  violet  colour,  while  narcotine  and  hydro- 
cotamine react  in  the  same  way  as  with  pure  acid. 

It  will  be  seen  that  several  of  the  reactions  described  by  Hesse 
differ  in  a  marked  manner  from  those  recorded  by  other  observers. 
As  in  the  case  of  other  colour-observations,  the  only  safe  way  is  to 
compare  the  substance  under  examination  side  by  side  with  pro- 
ducts of  known  purity. 

Lafon's  reagent,  prepared  by  dissolving  1  gramme  of 
ammonium  selenite  in  20  c.c.  of  strong  sulphuric  acid,  is  stated  by 
da  Sil  va  (Compt.  Rend.,  cxii.  1266)  to  give  the  following  colour- 
reactions  with  the  opium  bases : — Codeine,  magnificent  green 
coloration ;  morphine,  greenish  blue,  changing  to  chestnut  brown ; 
narcotine,  blue,  turning  violet  and  then  reddish,  with  slight  reddish 
precipitate  after  long  standing ;  nurceine,  yellowish  green,  changed 
to  brown  and  red,  with  red  precipitate  on  standing ;  papaveriney 
blue,  passing  to  dull  green,  violet  and  red,  with  a  slight  bluish 
precipitate  on  standing. 

Determination  and  Separation  of  Opium  Bases. 

Morphine,  codeine,  and  thebaine  may  be  titrated  with  ease  and 
accuracy  by  a  standard  mineral  acid,  using  litmus  or  methyl- 
orange  as  an  indicator  (page  130).  On  the  contrary,  they  have 
little  or  no  action  on  phenolphthalein,  the  reaction  with  which, 
however,  is  not  sharp  in  the  case  of  morphine  (page  311). 

Papaverine,  narcotine  and  narceine,  on  the  contrary,  do  not 
affect  Htmus,  and  their  salts  may  be  titrated  with  litmus  and  stan- 

^  Hesse  states  that,  when  absolutely  pure,  papaverine  dissolves  in  small 
quantities  of  sulphuric  acid  without  coloration  ;  but,  generally,  on  warming  a 
crystal  of  papaverine  with  concentrated  sulphuric  acid,  a  dark  blue  colour  is 
produced.  Dott  also  obtains  no  coloration  in  the  cold,  and  the  blue  coloiir 
on  strongly  heating  only.  A  red  coloration  before  heating  is  generally  due  io 
thebaine. 

VOL.  III.  PART  II.  Cr 


306  SEPARATION   OF   OPIUM  BASES. 

dard  alkali,  just  as  if  the  acid  were  uncombined  ( P 1  u  g  g  e, 
Pharm.  Jour.,  [3],  xx.  401);  and  the  first  two  of  them  being 
alkaloids  also  evince  their  feeble  basic  characters  by  the  fact  that 
they  are  extracted  by  chloroform  from  acid  solutions.  Their  salts, 
especially  with  certain  organic  acids  (e.g.,  acetic,  benzoic),  are  very 
unstable,  many  of  them  being  decomposed  slowly  by  cold  and  rapidly 
by  hot  water.  Hence,  when  a  compound  of  the  alkaloid  with  a 
mineral  acid  is  treated  with  a  neutral  solution  of  acetate  of  sodium, 
or  even  with  a  sHghtly  acid  solution,  the  free  alkaloid  is  precipitated.^ 
A  faintly  acid  solution  of  sodium  acetate  will  indicate  1  part  in 
40,000  of  narcotine,  1  in  30,000  of  papaverine,  and  1  in  600  of 
narceine,  none  of  the  other  opium  bases  being  precipitated. 

On  the  foregoing  and  similar  facts,  P.  C.  Plugge  {Analyst, 
xii.  197)  has  based  the  following  process  of  separating  the 
leading  alkaloids  of  opium.  The  aqueous  solution  of  the 
hydrochlorides  is  mixed  with  a  concentrated  solution  of  sodium 
acetate,  and  filtered  after  twenty-four  hours.  The  precipitate,  con- 
sisting of  pure  narcotine  and  papaverine,  is  washed  with  a  little 
water,  and  dissolved  in  a  minimum  of  dilute  hydrochloric  acid. 
The  liquid  is  diluted  till  it  contains  not  more  than  ;jJq  of  nar- 
cotine, when  potassium  ferricyanide  is  added.  This  precipitates 
papaverine  very  perfectly.  After  standing  twenty-four  hours  the 
liquid  is  filtered,  and  the  precipitate  of  papaverine  hydrof erri- 
cyanide  either  weighed  as  such,  or  washed  with  a  little  water, 
decomposed  by  dilute  caustic  soda,  and  the  liberated  alkaloid  dis- 
solved in  dilute  acid  and  reprecipitated  with  ammonia.  In  the 
filtrate  from  the  precipitate  produced  by  the  ferricyanide  the  nar- 
cotine is  precipitated  by  ammonia.  The  filtrate  from  the  precipi- 
tate produced  by  sodium  acetate  is  concentrated  to  a  small  volume 
at  100°,  cooled  thoroughly,  and  filtered  after  twenty-four  hours. 
The  deposited  narceine  is  filtered  off,  and  washed  with  a  little 
water.  The  filtrate  is  mixed  with  a  strong  solution  of  sodium 
salicylate,  and  the  crystalline  precipitate  of  thebaine  salicylate 
separated  after  twenty-four  hours,  and  washed  with  a  little  water, 
dried  at  100°,  and  weighed.  On  subsequent  treatment  on  the 
filter  with  dilute  soda  or  ammonia,  till  the  washings  are  free  from 
salicylic  acid  (as  indicated  by  evaporating  to  dryness,  and  the  non- 
production  of  a  violet  coloration   on  moistening  the  residue  with 

^  This  observation  is  due  to  P.  C.  Plugge  {Arch.  Pharm.,  [3],  xxiv.  994; 
Analyst,  xii.  197).  The  reaction  not  only  distinguishes  papaverine,  narcotine 
and  narceine  from  morphine,  codeine,  and  thebaine,  but  also  from  caflfeine, 
cocaine,  conine,  atropine,  pilocarpine,  strychnine,  brucine,  quinine,  cincho- 
nine  and  cinchonidine.  The  cinchona  bases  are  precipitated  if  the  sodium 
acetate  is  at  all  alkaline. 


SEPARATION  OF  OPIUM  BASES.  307 

ferric  chloride),  pure  thebaine  is  left.  The  filtrate  from  the  thebaine 
salicylate  is  acidulated  with  hydrochloric  acid,  the  precipitated 
salicylic  acid  filtered  ofi",  and  the  filtrate  repeatedly  shaken  with 
chloroform.  This  dissolves  the  remaining  sahcylic  acid,  and  traces 
of  narceine  and  thebaine,  which  may  be  recovered  by  evaporating 
the  cliloroform.  The  acid  hquid  separated  therefrom  is  concen- 
trated somewhat,  made  exactly  neutral  to  litmus,  and  mixed  with 
potassium  thiocyanate  (sulphocyanide),  which  throws  down  the 
codeine  as  an  acid  thiocyanate.  Twenty-four  hours  should  be 
allowed  for  its  complete  separation.^  The  filtrate  should  be  treated 
with  a  sUght  excess  of  ammonia,  and  time  allowed  for  the  separ- 
ated morphine  to  become  crystalline.  The  Hquid  is  then  shaken 
with  chloroform  or  ether  to  remove  the  remainder  of  the  codeine 
and  traces  of  other  bases.  After  separation  it  is  acidulated  to  dis- 
solve the  morphine,  heated  to  60°  C,  and  the  morphine  shaken 
out  with  hot  amylic  alcohol,  after  addition  of  a  slight  excess  of 
ammonia  or  carbonate  of  sodium.  Plugge's  results,  obtained  in 
test  experiments,  except  in  the  separation  of  codeine  and  morphine, 
were  very  satisfactory,  considering  the  difficult  nature  of  the  problem 
to  be  solved.  1  But  the  methods  are  not  to  be  regarded  as  having  the 
same  quantitative  accuracy  as  those  for  the  separation  of  the  metals. 

Another  method  of  separating  the  principal  alkaloids  of  opium 
consists  in  treating  the  solution  with  an  alkaline  carbonate  or  am- 
monia, and  agitating  with  benzene,  when  morphine  and  narceine 
are  left  insoluble,  the  remainder  passing  into  the  benzene.  Much 
the  same  separation  occurs  with  chloroform,  except  that  pseudo- 
morphine  is  left  with  the  insoluble  alkaloids. 

D.  B.  Dott  has  communicated  to  the  author  the  following 
method  of  separating  the  chief  bases  of  opium  : — Treat  the  solution 
of  their  mixed  hydrochlorides  with  a  10  per  cent,  solution  of  caustic 
soda,  and  wash  the  precipitate,  which  will  consist  of  narcotine, 
papaverine  and  thebaine,  the  alkaline  solution  containing  morphine, 
codeine  and  narceine.  On  agitating  the  filtrate  with  chloroform, 
the  codeine  will  be  extracted;  and  on  separating  the  alkaline 
Hquid,  acidulating  it,  and  rendering  it  faintly  alkaline  with 
ammonia,  the  morphine  wiU  be  precipitated,  the  narceine,  from 
its  greater  solubility,  remaining  dissolved.     It  can  be  recovered  by 

*  The  separation  of  codeine  and  morphine  by  this  process  is  very  imperfect. 
If  the  solution  be  too  strong,  morphine  is  precipitated  with  the  codeine,  and 
if  this  condition  be  avoided  the  precipitation  of  the  codeine  is  incomplete.  In 
test-experiments  Plugge  only  recovered  70  per  cent,  of  the  codeine  used. 
Hence  it  is  better  to  omit  the  precipitation  with  thiocyanate  altogether,  pre- 
cipitate the  morphine  with  ammonia,  and  extract  the  codeine  from  the  filtrate 
by  ether  or  chloroform,  after  adding  caustic  soda  (compare  page  323). 


308  SEPARATION  OF  OPIUM  BASES. 

evaporating  the  liquid  to  dryness  and  treating  the  residue  with  strong 
alcohol.  From  the  bases  precipitated  by  caustic  soda,  the  thebaine 
can  be  separated  fairly  well  by  crystallisation  as  acid  tartrate. 

Narcotine  and  papaverine  may  also  be  separated  from  thebaine 
(and  codeine)  by  dissolving  the  free  bases  in  dilute  alcohol,  rendering 
the  liquid  faintly  acid  with  acetic  acid,  and  adding  three  volumes  of 
boiling  water,  when  the  narcotine  and  papaverine  are  precipitated ; 
or  sodium  acetate  may  be  used  as  already  described.  Narcotine 
and  papaverine  may  likewise  be  separated  by  solution  in  boiling 
water  containing  one-third  part  of  oxalic  acid,  when  an  acid 
papaverine  oxalate  crystallises  out  on  cooling.  The  process  should 
be  repeated  several  times,  and  the  narcotine  finally  precipitated  by 
ammonia  and  crystaUised  from  boiling  alcohol. 

The  following  is  an  epitome  of  Hesse's  method  of  separating 
the  rarer  opium  bases  from  the  mother-liquors  left  from  the  prepara- 
tion of  morphine  by  the  Eobertson-Gregory  process.^  The 
aqueous  extract  of  opium  is  first  precipitated  by  calcium  chloride, 
the  filtrate  from  the  calcium  meconate  concentrated,  and  the 
hydrochlorides  of  morphine,  pseudomorphine  and  codeine  sepa- 
rated by  crystallisation.  The  mother-liquor  is  diluted  with  an  equal 
bulk  of  boiling  water,  excess  of  ammonia  added,  the  precipitate 
removed  by  filtration  and  dissolved  in  acetic  acid.  The  filtrate 
is  agitated  with  ether,  the  ethereal  layer  shaken  with  excess  of 
acetic  acid,  and  the  acetic  solution  mixed  with  that  of  the  ammonia 
precipitate.  The  acetic  acid  solution  is  then  treated  with  excess  of 
caustic  soda,  which  precipitates  papaverine,  narcotine,  thebaine, 
some  cryptopine,  protopine,  laudanosine  and  hydrocotarnine ; 
while  lanthopine,  laudanine,  codamine,  meconidine,  and  a  portion 
of  the  cryptopine  remain  in  solution.  The  alkaline  liquid  is 
neutralised,  ammonia  added,  the  bases  again  extracted  by  ether, 
and  shaken  out  with  acetic  acid.  The  acetic  acid  is  neutralised 
with  ammonia,  when  a  little  lanthopine  separates  out  in  twenty- 
four  hours,  and  the  filtrate  is  treated  with  more  ammonia.  The 
precipitate  formed  is  dissolved  in  a  very  small  quantity  of  boiling 
dilute  alcohol,  which  on  cooling  deposits  white  crystals  of  mixed 
laudanine  and  cryptopine.  On  evaporating  the  alcoholic  solution,^ 
and  treatment  of  rhe  residue  with  ether,  a  solution  is  obtained 
from  which  codamine  may  be  isolated,  either  by  addition  of  fused 

*  For  E.  Kauder'a  modification  of  Hesse's  method,  see  Arch.  Pharm., 
ocxxviii.  419  ;  and  Jour.  Ghem,  Soc.j  Ix.  227, 

2  Hesse  could  obtain  no  meconidine  from  this  solution,  and  hence  concludes 
that  it  had  been  decomposed  by  the  preceding  operations,  as  he  had  pre- 
viously obtained  it  from  a  similar  source  by  another  process  {Ann.  Ghem. 
Pharm.,  cliii.  47  ;  Watts'  Diet.  Ghem.,  vi.  883). 


SEPARATION   OF   OPIUM  BASES.  309 

calcium  chloride  (which  causes  water,  colouring-matter,  and  crystals 
of  codamine  to  separate),  or  by  conversion  into  the  acetate,  and 
this  into  the  hydriodide. 

The  mixture  of  bases  insoluble  in  caustic  soda  is  digested  with 
dilute  alcohol,  and  acetic  acid  added  till  the  liquid  is  faintly  acid  to 
litmus.  On  adding  three  measures  of  boiling  water,  a  crystalline 
precipitate  of  papaverine  and  narcotine  is  thrown  down.  The 
filtrate,  freed  from  alcohol  by  evaporation,  on  adding  strong  hydro- 
chloric acid,  will  give  a  precipitate  of  cryptopine  hydrochloride ;  but 
in  order  to  avoid  the  conversion  of  thebaine  into  its  non-crystalline 
isomer  thebaicine,  it  is  preferable  to  add  tartaric  acid,  which 
throws  down  crystalline  tliehaine  acid  tartrate.  The  mother-liquor 
of  this  is  neutralised  with  ammonia,  and  mixed  with  3  per  cent, 
of  its  weight  of  sodium  bicarbonate  made  into  a  paste  with  water. 
After  standing  about  a  week,  a  black,  pitchy  mass  separates,  the 
filtrate  from  which  gives  with  ammonia  a  precipitate  which  is 
treated  with  boiling  benzene,  the  filtrate  being  also  extracted  by 
agitation  with  benzene.  On  shaking  the  united  benzene  solution 
with  a  saturated  aqueous  solution  of  sodium  bicarbonate,  laudano- 
sine  crystallises  out;  and  the  benzene  filtered  from  this  yields 
hydrocotarnine  hydrochloride  on  passing  hydrochloric  acid  gas. 
The  portion  of  the  ammonia  precipitate  left  undissolved  by  benzene 
contains  cryptopine  and  protopine.  These  bases  are  converted  in 
nydrochlorides,  and  the  solution  treated  with  strong  hydrochloric 
acid,  when  the  protopine  hydrochloride  forms  a  horny  deposit  which 
adheres  to  the  sides  of  the  glass,  and  is  easily  freed  from  the 
gelatinous  cryptopine  salt  by  washing  with  a  little  water. 

Narceine  is  mentioned  as  existing  in  the  liquors,  but  the  stage 
at  which  it  is  separated  is  not  stated. 

Morphine.      Morphia. 

CiyHigNOg;  Ci7Hi7NO(OH)2  ;  or  Ci7Hi/0H)N0.0H. 

Morphine  is  the  most  important  of  the  bases  contained  in  opium, 
in  which  it  exists  in  combination  with  sulphuric  and  meconic  acids. 

The  mode  of  preparing  morphine  may  be  gathered  from  the 
methods  of  assaying  opium  (see  also  last  page). 

Morphine  crystallises  in  transparent,  colourless,  trimetric  prisms, 
which  are  usually  very  short.  They  contain  one  molecule  of  water, ^ 
which  is  given  off  slowly  at  a  temperature  of  90°  and  more  rapidly  at 
100°  C.  {Pharm.  Jour.,  [3],  xviii.  701,  801  ;  xix.  61,  148,  180). 
At  or  above  200°  morphine  partially  volatilises,  melts,  and  turns 
brown,  becoming  carbonised  at  a  somewhat  higher  temperature. 

^  D.  B,  Dott  found  the  proportion  of  water  lost  to  correspond  more  nearly 
toSCyHigNOg  +  QHsO. 


310 


SOLUBILITIES  OF   MORPHINE. 


Morphine  is  inodorous,  has  a  persistent  bitter  taste,  and  is  a 
powerful  narcotic  poison. 

Morphine  is  nearly  insoluble  in  cold  water,  requiring,  according 
to  Chastaing,  33,333  parts  at  3°  and  4545  at  22V  At  42°, 
the  solubility  is  1  in  2380,  and  in  boiling  water  about  1  in  460 
{Year- Booh  Pharm.,  1882,  p.  30).  The  solution  has  an  alkaline 
reaction.  Morphine  dissolves  in  30  parts  of  boiling  or  50  of  cold 
absolute  alcohol,  and  in  a  somewhat  smaller  quantity  of  rectified 
spirit.'  In  ether  and  chloroform  it  is  almost  insoluble  when  in  a 
crystallised  state,  but  dissolves  sparingly  when  freshly-precipitated 
and  amorphous.  A  useful  solvent  for  morphia  is  a  mixture  of 
equal  volumes  of  ether  and  acetic  ether  (ethyl  acetate) ;  but  even 
in  this  its  solubility  is  limited,  especially  in  the  crystalline  state. 
Amylic  alcohol  dissolves  morphine  sparingly  (1  :  150)  in  the  cold, 
but  when  heated  is  a  fairly  good  solvent  for  it  (1  :  50).  The 
alkaloid  dissolves  best  when  liberated  from  one  of  its  salts  in 
presence  of  amylic  alcohol. 

In  benzene  and  petroleum  spirit,  morphine  is  practically  insoluble, 
as  also  in  volatile  oils. 

According  to  Florio  {Gaz.  Cliim.  Italiano^  xiii.  496)  100 
parts  of  the  following  solvents  dissolve  of  morphine  : — 


Solvent. 

Morphine  dissolved  by  100  of  Solvent. 

At  10°-11°  C. 

At  56"  C. 

At  78°  C. 

Alcohol,  absolute,   .... 

„         90  per  cent.,      , 

„        75  per  cent., 

Wood -spirit, 

Fusel-oil, 

Benzene 

Chloroform 

Ether,  absolute,       .... 

1-132 
0-377 
0-223 
1-675 
0-268 
0-020 
0040 
0-023 

8-466 
3-235 

8-623 
2-991 
1-985 

2-247 

A.  B.  Prescott  {Jour.  Chem.  Soc,  xxix.  405)  has  pointed 
out  the  great  influence  the  physical  condition  of  morphine  has 
upon  its  relation  to  solvents,  and  has  determined  the  proportion 
of  different  solvents  requisite  for  the  solution  of  morphine  in  the 
crystalline,  amorphous,  and  "  nascent "  conditions ;  by  the  last 
term  meaning  that  in  which  the  alkaloid  exists  when  liberated  by 
ammonia  or  an  alkaline  carbonate  from  the  aqueous  solution  of 
one  of  its  salts.     The  following  are  Prescott's  figures : — 


Dott  gives  the  solubility  of  morphine  in  water  at  15°  C.  as  1  in  2500. 


PROPERTIES  OF   MORPHINE. 


311 


Condition  of  the  Morphine. 

Parts  of  Solvent  required. 

Ether.          Chloroform. 

1 

Crystallised,      . 
Amorphous  powder, . 
"Nascent  "state,      . 

6148 
2112 
1062 

4379 
1977 
861 

91 
91 

8930 
1997 

Other  figures  for  the  solubility  of  morphine  are  given  on  page  301. 

Solutions  of  caustic  potash  and  soda  dissolve  morphia  readily, 
as  also  do  baryta  and  lime  water,  and,  to  a  limited  extent,  am- 
monia also.  Solutions  of  caustic  alkalies  dissolve  quantities  of 
morphine  equivalent  to  the  bases  contained  in  them,  with  the 
formation  of  unstable  morphinates  which  are  decomposed  by 
carbonic  acid  and  assume  a  dark  brown  colour  on  exposure  to  air. 
Crystalline  morphinates  of  potassium,  barium,  and  calcium  have 
been  obtained.  From  these  facts,  and  the  blue  reaction  with  ferric 
chloride,  Chastaing  (Jour.  Pharm.,  [5],  iv.  19)  inferred  that 
morphine  possessed  a  phenoloid  character,  and  this  view  has  been 
fully  borne  out  by  the  later  researches  of  Grimaux  and  Hesse 
(page  296). 

Solutions  of  morphine  are  IsBvo-rotatory.  In  alcoholic  or  dilute 
acid  solution,  S^  is  said  to  be  —  89°'8  and  8^—70°.  For  the 
hydrochloride,  the  value  is  S„=  -  100°-67  -T'U  C.  In  alka- 
line solution,  the  value  of  Sr  for  morphine  is  stated  to  be  —45° "2. 

Morphine  is  very  sensitive  to  the  action  of  oxidising  agents,  a 
fact  which  is  often  used  for  its  detection  (page  314  et  seq.).  It 
reduces  salts  of  gold  and  silver,  permanganates,  ferricyanides,  iodic 
and  periodic  acids,  &c.  The  reactions  of  morphine  with  strong 
sulphuric  and  nitric  acids  are  described  on  pages  313,  314. 

When  morphine  is  heated  with  strong  hydrochloric  acid  or  zinc 
chloride  it  loses  the  elements  of  water  and  is  converted  into 
apomorphine,  C^yHj^NOg  (page  3 1 9). 

Salts  of  Morphine. 

Morphine  dissolves  readily  in  dilute  acids,  forming  salts  which 
are  perfectly  neutral  in  reaction  to  litmus  and  methyl-orange,  and 
hence  it  may  be  titrated  with  accuracy  by  the  aid  of  standard 
hydrochloric  acid  and  either  of  these  indicators.  With  phenol- 
phthalein  morphine  does  not  give  a  sharp  reaction,  but  the  point 
of  neutrality  is  approximately  the  same  as  if  the  acid  of  the 
morphine  salt  were  in  a  free  state. 

The  salts  of  morphine  are  mostly  crystallisable,  and  are  all  bitter 
and  very  poisonous.     They  are  generally  soluble  in  water  and   in 


312 


SALTS   OF  MORPHINE. 


alcohol,  but  are  insoluble  or  only  slightly  soluble  in  amylic  alcohol, 
ether,  chloroform,  benzene,  or  petroleum  spirit.  Morphine  is  not 
removed  from  its  acid  or  neutral  solutions  by  agitation  with  any 
of  the  above  solvents,  except  imperfectly  by  amylic  alcohol. 

The  following  table  shows  the  formulae  of  the  more  important  salts 
of  morphine,  the  percentage  of  morphine  hydrate,  the  relative  dose, 
and  D.  B.  Dott's  figures  for  their  solubility  in  cold  water 
(Pharm.  Jour.,  [3],  xiii.  404 ;  xvi.  653)  : — 


Morphine  Salt. 

Formula. 

Morphine 
Hydrate, 
per  cent. 

Relative 
Dose. 

SolubUity  in 
Water  at  15°-5  C. 

Hydrochloride, 

BHCl  +  3H2O 

80-69 

1-00 

1  part  in  24. 

Sulphate, 

B2,H2S04  +  5H2O 

79-94 

1-00 

„         23. 

Acetate,         .       . 

B,C2H402  +  3H2O 

75-93 

104 

2i. 

Lactate,  . 

B.CsHeOg 

80-80 

1-00 

8. 

Tartrate, 

B2,C4H606  +  3H2O 

78-29 

1-02 

9f. 

Meconate, 

B2,C7H407  +  5H2O 

70-46 

1-14 

„          34. 

illf(9r^Mwe-H2/^^^^^^<^^*'^^>  or  Morphia  Hydrochlorate,  BHCl  +  3H2O, 
crystallises  in  colourless  silky  fibres,  soluble  in  half  its  weight  of 
boiling  water  and  in  40  parts  of  cold  rectified  spirit.  It  becomes 
anhydrous  at  100°  C.  The  commercial  salt  often  has  a  buff  01 
brownish  tint  from  admixture  of  resinous  matters,  which  are 
detected  by  the  brown  or  black  colour  assumed  by  the  salt  when 
heated  to  130°  C. 

Morphine  Hydriodide,  BHI  +  SHgO,  is  obtained  as  a  compact 
mass  of  hair-like  needles  on  mixing  a  concentrated  alcoholic  solu- 
tion of  potassium  iodide  with  a  concentrated  solution  of  morphine 
hydrochloride.  The  product  only  slowly  redissolves  on  adding 
more  spirit,  and  is  very  sparingly  soluble  in  water,  especially  in 
presence  of  potassium  iodide.  The  hydrobromide  can  be  obtained 
similarly. 

Morphine  Sulphate,  B2H2SO4  +  5H2O,  closely  resembles  the 
hydrochloride.  It  loses  3H2O  at  100°,  and  the  remaining  two 
atoms  at  110°.     It  exists  naturally  in  opium. 

Morphine  Acetate  (see  above)  is  a  white,  or  faintly  yellowish 
white,  obscurely  crystalline  powder.  It  is  readily  soluble  and 
crystallisable.  It  is  partially  decomposed  by  boiling  or  evaporating 
its  aqueous  solution,  crystals  of  morphine  being  deposited. 

Morphine  Tartrate,  BgC^HgOg -h  SHgO,  is  readily  soluble,  but 
the  acid  tartrate,  BC^HgOg,  only  sparingly  so.  Their  solutions  are 
not  precipitated  by  caustic  alkalies,  alkaline  carbonates,  or  chloride 


REACTIONS  OF  MORPHINE.  313 

of  calcium.  The  tartrate  is  best  detected  by  precipitating  the  con- 
centrated solution  with  potassium  acetate  and  acetic  acid  in 
presence  of  alcohol  (Yol.  I.  page  457).  After  boiling  off  the 
alcohol,  the  morphia  can  be  precipitated  from  the  filtrate  by  an 
alkaline  carbonate  or  ammonia. 

Morphine  Meconate  (see  above)  is  interesting  as  being  the  form 
in  which  morphia  largely  exists  in  opium.  When  morphine  and 
meconic  acid  are  dissolved  in  absolute  alcohol,  and  the  solution  is 
evaporated,  an  amorphous,  hygroscopic,  very  soluble  residue  is 
obtained,  which  in  concentrated  sohition  deposits  crystals  of  neutral 
morphine  meconate  containing  5  aqua,  even  in  presence  of  suffi- 
cient meconic  acid  to  form  the  acid  salt. 

Detection  and  Determination  of  Morphine. 

Free  morphine,  when  pure  or  in  the  form  of  one  of  its  ordinary 
salts,  is  readily  detected.  Its  determination  is  easy  when  un- 
mixed with  interfering  substances,  but  as  it  exists  in  opium  is 
attended  with  considerable  difficulties.  Most  of  the  colour-reactions 
of  morphia  are  best  observed  by  operating  on  the  solid  substance, 
but  for  certain  qualitative  tests  and  for  ail  quantitative  methods  the 
alkaloid  must  be  in  solution. 

A.  Reactions  of  Solid  Morphine,  For  observing  these  reactions 
a  minute  fragment  or  crystal  of  the  solid  alkaloid  or  its  salt  should 
be  employed,  and  the  experiment  should  be  conducted  in  a  small 
porcelain  basin  or  crucible.  The  residue  obtained  by  the  evapora- 
tion of  the  solution  of  morphine  in  alcohol  or  amylic  alcohol  is 
well-suited  for  the  operation. 

1.  Solid  morphine  treated  with  a  drop  of  a  perfectly  neutral  solu- 
tion of  ferric  chloride  or  iron-alum  gives  a  very  characteristic 
deep  greenish  blue  colour,  changed  to  green  by  excess  of  the  re- 
agent. The  colouring  matter  is  not  taken  up  by  chloroform.  The 
colour  is  destroyed  by  free  acid,  by  heat,  or  by  contact  with 
alcohol.^  Pseudomorphine  also  gives  a  blue  colour  with  ferric 
chloride,  and  codamine  a  dark  green. 

2.  Nitric  acid  (1"42  sp.  gr.)  added  to  solid  morphia  turns  it  an 
orange-red  colour,  which  is  changed  to  yellow  on  heating,  and 
destroyed   on   adding  sodium  thiosulphate   (hyposulphite).      The 

*  The  coloration  is  produced  in  strong  solutions  of  morphine,  but  becomes 
imperceptible  with  moderate  dilution.  J.  L.  Armitage  {Pharm.  Jour. ,  [3], 
xviii.  761)  has  pointed  out  that  even  in  solutions  far  too  dilute  to  give  the 
reaction,  the  morphine  may  be  detected  by  adding  potassium  ferricyanide, 
which  produces  a  blue  or  green  coloration.  Armitage  attributes  this  reaction 
to  the  reduction  of  the  iron  to  the  ferrous  state,  and  the  reaction  of  this 
with  the  ferricyanide  to  form  Turnbull's  blue  ;  but  it  is  more  probable  that 
the  ferricyanide  is  reduced  to  ferrocyanide,  and  then  reacts  with  the  ferric  salt 
to  form  Prussian  blue  (compare  page  31 7). 


314  COLOUR-REACTIONS   OF   MORPHINE. 

coloration  is  said  to  he  due  to  the  formation  of  a  body  of  the 
formula  CjoHgNOg,  which  yields  picric  acid  when  heated  with 
water  to  100°. 

3.  Solid  morphine,  when  pure,  is  commonly  said  to  yield  no 
coloration  in  the  cold  on  adding  pure  concentrated  sulphuric  acid ; 
but  according  to  Dott  {Pharm.  Jour.,  [3],  xii.  615)  a  distinct, 
though  faint,  pink  colour  is  produced.  On  heating  to  150°,  a 
dirty  green  (or  rose-red)  colour  is  developed,  and  on  raising  the 
temperature  still  further  the  solution  becomes  almost  black.  On 
allowing  it  to  cool  and  diluting  with  water,  a  greenish  blue  colour 
is  produced,  wliich  on  addition  of  ammonia  in  excess  becomes 
green. 

4.  On  adding  oxidising  agents  to  the  solution  of  solid  morphine 
in  cold  concentrated  sulphuric  acid,  the  following  reactions  are  pro- 
duced.-^ a.  After  adding  a  drop  or  two  of  water  to  heat  the  mix- 
ture, the  subsequent  addition  of  nitric  acid  will  produce  a  rose-red 
coloration,  changing  to  brown.  The  reaction  is  very  delicate. 
h.  Potassium  chlorate  gives  reactions  similar  to  those  with  nitric 
acid.  If  the  alkaloid  be  first  heated  with  concentrated  sulphuric 
to  100°  for  half  an  hour,  and  a  crystal  of  potassium  chlorate  or 
nitrate  added  to  the  previously  cooled  violet-red  solution,  a  beau- 
tiful violet-blue  colour  is  produced,  which  passes  into  a  dark  blood- 
red,  changing  to  yellow,  c.  If  the  sulphuric  acid  solution  be  heated 
on  the  water-bath  to  100°,  and  a  minute  fragment  of  pure  potassium 
perchlorate^  be  added,  a  deep  brown  or  reddish  brown  coloration 
is  produced,  which  rapidly  spreads  through  the  liquid.  The  colour 
is  destroyed  on  dilution.  L.  S  i  e  b  o  1  d,  to  whom  the  test  is  due,  did 
not  observe  a  similar  reaction  with  any  other  alkaloid,  d.  Potas- 
sium bichromate  is  reduced  with  production  of  green  colour.  (No 
colour-reaction  is  produced  if  for  the  bichromate  be  substituted  the 
dioxide  of  lead  or  manganese.  Distinction  from  strychnine.)  e.  On 
adding  sodium  or  potassium  arseniate,  and  warming  gently,  a  slate- 
blue  colour  is  produced,  which  on  raising  the  temperature  passes 
into  green,  then  into  deep  blue,  and  finally,  when  the  acid  begins 
to  volatilise,  again  into  dark  olive-green.  On  diluting  moderately 
with  water,  a  reddish  brown  coloration  is  produced,  changing  to  dirty 
bluish  and  green  on  further  dilution ;  and  on  agitating  with  chloro- 
form the  latter  liquid  is   coloured    violet-blue   (D  o  n  a  t  h).      If 

1  The  reactions  in  question  have  been  verifieci  in  the  author's  laboratory 
byW.  H.  Barraclough,  and  the  description  given  in  the  text  is  in  accord- 
ance with  his  results. 

^  The  perchlorate  must  be  free  from  chlorate,  which  is  ensured  by  heating  it 
with  hydrochloric  acid  as  long  as  chlorine  is  evolved.  The  salt  is  then  washed 
with  cold  water  and  dried. 


COLOUR-REACTIONS  OF  MORPHINE.  315 

sodium  phosphate  be  substituted  for  the  arseniate^  and  heat 
applied  till  acid  fumes  appear,  the  mixture  becomes  violet,  chang- 
ing to  brown  or  olive-green.  If,  after  cooling,  water  be  gradually- 
added,  a  reddish  brown  coloration  appears,  changing  to  dirty  bluish 
green  on  further  dilution.  On  now  shaking  with  chloroform,  the 
latter  liquid  acquires  a  fine  blue  colour.  /.  Sodium  or  ammonium 
molybdate  added  to  the  sulphuric  acid  solution  gives  a  fine  violet 
coloration,  changing  to  blue  and  dirty  green,  and  finally  almost 
vanishing.  The  reaction  of  morphine  with  sulphomolybdic  acid 
may  be  observed  with  more  certainty  by  adding  previously  pre- 
pared Frohde's  reagent  (page  147)  to  the  solid  morphine.  Papa- 
verine and  a  few  glucosides  give  a  similar  reaction. 

5.  If  solid  morphine  be  mixed  with  from  2  to  8  parts  of 
powdered  cane-sugar,  or  solutions  of  the  two  bodies  be  mixed  and 
evaporated  to  dryness,  addition  of  a  drop  of  concentrated  sulphuric 
acid  wiU  produce  a  beautiful  purple  colour,  changing  gradually  to 
blood-red  and  brownish  red,  becoming  olive-brown  on  dilution  with 
water.  The  colouring  matter  is  not  soluble  in  chloroform.  The 
test  may  be  applied  to  a  solution  of  morphine  by  saturating  the 
liquid  with  sugar,  and  pouring  it  carefully  on  to  some  concentrated 
sulphuric  acid,  when  a  purple  or  rose-red  coloration  will  be  ob- 
served at  the  junction  of  the  two  fluids.  Codeine  gives  a  very 
similar  reaction  (Schneider).  According  to  H.  W  e  p  p  e  n  the 
delicacy  of  this  test  is  much  increased  by  adding  a  drop  of  bromine- 
water  after  the  sulphuric  acid,  this  modification  rendering  the 
reaction  equal  if  not  superior  to  reactions  3  and  4  c,  and  less 
dependent  on  the  purity  of  the  morphia. 

M.  Robin  mixes  the  alkaloid  with  twice  its  weight  of  powdered 
sugar,  and  adds  one  or  two  drops  of  pure  sulphuric  acid,  and  states  that 
morphine  hydrochloride  gives  a  beautiful  rose  colour,  changing  first 
to  the  tint  of  a  solution  of  potassium  permanganate,  and  then  to 
violet  and  dark  green,  while  codeine  gives  a  cherry-red  colour 
changing  to  violet,  and  narcotine  a  beautiful  and  very  persistent 
mahogany-brown  colour.^ 

B.  Reactions  of  Morphine  in  solution.     The  following  reactions 

1  For  convenience,  this  test  is  described  here,  but  it  seems  improbable  that 
the  reaction  is  due  to  oxidation. 

2  Atropine  gives  with  sugar  and  sulphuric  acid  a  violet  coloration,  changing 
to  brown  ;  veratrine,  a  deep  green  ;  santonin,  a  red  colour,  changing  to  cofFee- 
black.  Salicin  gives  a  vivid  red.  Pure  aconitine  gives  no  reaction,  but 
mixed  aconite  alkaloids  as  extracted  from  the  root  give  a  fine  cherry-red 
coloration,  changing  to  crimson.  No  reaction  is  given  by  strychnine,  brucine, 
cocaine,  pilocarpine,  caffeine,  beberine,  apomorphine,  cupreine,  or  the  cin- 
chona bases  (J.  F.  Burnett). 


316  DETERMINATION   OF  MORPHINE. 

are  yielded  by  an  aqueous  solution  of  the  hydrochloride  or  acetate 
of  morphine : — 

1.  On  adding  to  a  tolerably  concentrated  solution  of  a  salt  of 
morphine  a  fixed  caustic  alkah,  an  alkaline  carbonate,  ammonia, 
or  lime-water,  hydrated  morphine,  Cj^H^gNOg  +  HgO,  is 
thrown  down  as  a  white  precipitate  speedily  becoming  crystalline. 
The  precipitate  is  almost  insoluble  in  perfectly  cold  water,  but 
dissolves  in  excess  of  ammonia  or  lime-water,  and  very  readily  in 
excess  of  caustic  alkali.  The  alkaline  carbonates,  used  in  excess, 
redissolve  the  precipitate  somewhat,  but  it  is  insoluble  in  excess  of 
bicarbonates.  Excess  of  magnesia  precipitates  the  alkaloid  com- 
pletely. The  morphia  precipitated  by  the  foregoing  reagents,  and 
allowed  time  to  become  crystalline,  presents  a  characteristic  appear- 
ance under  the  microscope. 

A  fairly  accurate  determination  of  morphine  may  be  made  in 
the  absence  of  interfering  substances,  by  precipitating  the  tolerably 
concentrated,  cold,  aqueous  solution  with  sodium  bicarbonate,  allow- 
ing time  for  the  precipitate  to  become  crystalline,  filtering,  washing 
moderately  with  very  cold  water  (preferably  saturated  with  mor- 
phine), drying  at  100°  or  120°,  and  weighing  the  anhydrous 
morphine,  C^^H-^gNOg,  when  the  weight  becomes  constant. 

Instead  of  drying  and  weighing  the  alkaloid,  the  washed  preci- 
pitate may  be  placed,  together  with  the  filter,  in  a  moderate  excess 
of  standard  acid,  and  the  excess  employed  ascertained  by  titration 
with  litmus  or  methyl-orange  (not  phenolphthalein).  1  c.c. 
of  decinormal  acid  neutralises  0'0285  gramme  of  anhydrous 
morphine. 

2.  If  morphia  be  liberated  from  the  solution  of  a  salt  by  one  of 
the  reagents  mentioned  above,  and  the  liquid  and  suspended  pre- 
cipitate be  at  once  shaken  with  hot  amylic  alcohol,  cold  acetic 
ether,  or  a  mixture  of  equal  measures  of  ether  and  acetic  ether,^ 
the  morphia  passes  into  solution,  though  with  some  difiiculty,  and 
may  be  obtained  in  a  free  state  by  separating  the  ethereal  liquid, 
and  evaporating  it  to  dryness  at  a  gentle  heat.  If  the  liberated 
morphia  be  allowed  to  crystallise  before  subjecting  it  to  agitation 
with  the  solvent,  its  solution  becomes  very  difficult  to  effect. 

For  quantitative  purposes,  hot  amylic  alcohol  should  be  employed 
as  the  solvent.  It  should  be  added  before  the  alkaloid  is  liberated, 
which  should  be  done  by  ammonia,  magnesia  or  sodium  bicarbonate, 
and  the  agitation  should  be  conducted  immediately,  and  the  separa- 
tion and  re-agitation  effected  without  delay.  On  evaporation  of 
the  amylic  alcohol  at  100°  the  anhydrous  morphine  will  remain  as 

^  The  acetic  ether  must  be  free  from  acid.    This  may  be  ensured  by  agitating 
it  with  some  sodium  bicarbonate  before  use. 


REACTIONS  OF  MORPHINE.  317 

a  residue,  which  can  be  weighed,^  or  the  amylic  alcohol  containing 
the  alkaloid  in  solution  may  be  titrated  by  dilute  standard  acid 
and  methyl-orange,  as  described  on  page  131.  If  desired,  the 
alkaloid  may  be  recovered  from  its  amylic  alcohol  solution  by 
repeated  agitation  with  dilute  hydrochloric  acid,^  and  then  repre- 
cipitated  from  the  aqueous  liquid  by  ammonia,  or  an  alkaline 
bicarbonate.  This  affords  a  valuable  means  of  purifying  morphine 
and  separating  it  from  other  alkaloids. 

To  effect  complete  extraction  of  the  morphine  liberated  by 
magnesia,  ammonia,  or  an  alkaline  bicarbonate,  several  agitations 
with  amylic  alcohol  are  necessary.  If  ammonia  be  employed, 
sufficient  passes  into  the  amylic  alcohol  bo  vitiate  the  subsequent 
determination  of  the  morphine  by  titration ;  while  if  the  amylic 
alcohol  be  freed  from  ammonia  by  agitation  with  water,  or  even  with 
brine,  a  portion  of  the  morphine  is  dissolved  out.  If  the  separated 
amylic  alcohol  be  distilled  off,  the  residual  morphine  may  be  titrated, 
or  the  difficulty  avoided  by  using  magnesia  instead  of  ammonia. 

3.  A  volumetric  determination  of  morphine  may  be  made  by 
means  of  Mayer's  solution,  as  described  on  page  140.  The  method 
has  little  practical  utility. 

Further  information  on  the  determination  of  morphine  will  be 
found  in  the  section  on  the  assay  of  opium. 

4.  Morphine  readily  reduces  ferricyanides  to  ferrocyanides,  with 
formation  of  pseudomorphine  (oxydimorphine)  : — 

4C17H19NO3, HCl  +  4K3FeCye = 2(C34H3,,N206, 2 HCl)  +  3K4FeCy6  +  H4FeCye  . 
Consequently,  on  adding  to  the  solution  of  a  salt  of  morphine, 
slightly  acidulated  with  hydrochloric  acid,  a  mixture  of  aqueous 
solutions  of  ferric  chloride  and  potassium  ferricyanide,  a  blue 
coloration  or  precipitate  of  Prussian  blue  is  produced.  This  reaction 
may  be  conveniently  employed  for  detecting  morphine  in  presence 
of  the  cinchona  bases. 

L.  Kieffer  {Annal.  Ohem.  Pharm.,  ciii.  274)  has  proposed  to 
utilise  the  reaction  with  ferricyanide  for  the  quantitative  deter- 
mination of  morphine.  For  this  purpose  he  adds  a  known  weight 
of  solid  potassium  ferricyanide  to  the  morphine  or  its  salt,  and 
mixes  them  in  a  mortar  with  a  minimum  quantity  of  water.  The 
contents  of  the  mortar  are  rinsed  into  a  flask,  potassium  iodide 
and  hydrochloric  acid  added,  and  the  liberated  iodine  determined 

^  There  is  some  evidence  that  morphine  forms  a  compound  with  amylic 
alcohol  not  decomposed  by  evaporation  at  the  ordinary  temperature  {Pharm, 
Jour.,  [3],  xviiL  161). 

'^  A  solution  of  morphine  in  hydrochloric  acid  cannot  be  shaken  with  amylic 
alcohol  without  extraccion  of  some  of  the  alkaloid,  probably  in  the  form  of 
hydrochloride. 


318  IODIC   ACID   TEST   FOR   MORPHINE. 

by  decinormal  sodium  thiosulphate  (hyposulphite).  The  difference 
between  the  volume  required  and  that  used  in  a  blank  experiment 
with  the  same  weight  of  potassium  ferricyanide  corresponds  to  the 
salt  reduced  by  the  morphine.  One  c.c.  of  difference  in  the  f^ 
thiosulphate  used  represents  '0292  of  anhydrous  morphine.^ 

Venturini  (Gaz.  Chim.  ItaL^  xvi.  239)  reports  favourably  of 
Kieffer's  process.     The  author's  results  were  discouraging. 

6.  On  mixing  a  solution  of  morphine  with  one  of  iodine  dis- 
solved in  hydriodic  acid,  a  crystalline  precipitate  is  formed  even  in 
extremely  dilute  solutions.  Under  the  microscope  the  crystalline 
form  is  characteristic  of  morphine,  which  may  thus  be  distinguished 
from  papaverine  and  codeine,  which  bases  also  give  crystalline  pre- 
cipitates with  the  reagent,  while  narcotine,  narceine  and  thebaine 
yield  amorphous  precipitates. 

6.  Addition  of  chlorine  or  bromine  water,  followed  by 
ammonia,  occasions  in  moderately  concentrated  solutions  of 
morphine  a  brown  colour  or  red  coloration  gradually  changing 
to  brown. 

7.  Morphine  and  its  salts  reduce  iodic  acid  with  liberation  of 
iodine.  This  reaction  is  also  produced  by  albuminoid  and  various 
other  organic  bodies,  so  that  it  is  not  absolute  proof  of  the  presence 
of  morphia.  The  test  becomes  much  improved  and  increased  in 
delicacy  by  the  following  mode  of  operating : — 

To  the  solution  to  be  tested  for  morphia,  as  nearly  neutral  as 
possible,  is  added  one  of  iodic  acid  in  15  parts  of  water.  In 
presence  of  1  part  of  morphia  in  20,000  of  liquid  a  yellow  colora- 
tion is  observed.  In  moderately  strong  solutions  of  morphine 
addition  of  starch-liquor  gradually  changes  the  yellow  colour  to 
blue,  but  not  in  solutions  containing  less  than  1  per  1000.  This 
is  important,  as  with  other  reducing  agents  the  blue  colour  is  well 
marked  in  far  more  dilute  liquids.  On  adding  excess  of  ammonia 
to  the  yellow  liquid  the  colour  is  discharged  if  due  to  foreign 
matter,  but  distinctly  deepened  if  due  to  morphia.  If  a  solution  of 
morphine,  which  is  too  dilute  to  give  a  blue  colour  with  iodic  acid 
and  starch,  be  mixed  with  these  reagents,  and  some  highly  dilute 
ammonia  allowed  to  flow  from  a  pipette  on  to  the  surface  of  the 
liquid,  two  coloured  rings  make  their  appearance  at  the  junction  of 
the  fluids.  A  blue  ring  is  seen  in  the  lower  acid  layer  and  a  brown 
one  in  the  upper  alkaline  portion.  If  a  dilute  solution  of  morphia 
be  mixed  with  one  of  starch,  and  evaporated  to  dryness  in  a  por- 
celain crucible  at  a  gentle  heat,  and  the  residue,  after  cooHng,  be 

*  It  is  possible  that  Kieffer's  process  might  be  applied  to  the  amylic  alcohol 
solution  of  morphine,  by  agitating  it  with  potassium  ferricyanide  solution. 
In  such  a  case,  ammonia,  if  present,  would  not  interfere. 


APOMORPHINE.  319 

moistened  with  iodic  acid,  a  blue  colour  will  be  produced  in  pre- 
sence of  1-20,000  of  a  grain  of  morphia  (A.  Dupr^). 

Another  way  of  employing  the  test  is  to  agitate  a  solution  of 
iodic  acid  with  an  equal  measure  of  carbon  disulphide,  which 
should  not  become  coloured  even  after  adding  a  drop  or  two  of  dilute 
sulphuric  acid  and  again  shaking,  If  the  solution  to  be  tested  for 
morphine  be  now  added  to  the  mixture,  and  the  whole  again  shaken, 
the  carbon  disulphide  will  be  found  after  separation  to  have  a  violet 
colour  from  dissolved  iodine  if  morphine  be  present,  and  the  depth 
of  tint  will  afford  an  indication  of  the  amount.  Morphine  can  be 
recognised  in  this  way  in  a  single  drop  of  paragoric  or  tincture  of 
opium. 

Stein  and  others  have  described  a  colorimetric  method  of 
estimating  morphine,  based  in  the  iodic  acid  reaction. 

In  employing  the  iodic  acid  test  it  is  essential  that  the  reagent 
should  not  give  free  iodine  on  treatment  with  a  drop  of  dilute 
sulphuric  or  acetic  acid. 

8.  Solutions  of  morphine  salts  give  no  crystalline  precipitate  with 
either  potassium  chromate,  thiocyanate  (sulphocyanide)  or  ferro- 
cyanide  (distinction  from  strychnine). 

Apomokphine,  CiyHiyNOg.  When  morphine  or  its  hydro- 
chloride is  heated  to  140°-150°  C.  in  a  sealed  tube,  with  a  large 
excess  of  strong  hydrochloric  acid,  or  with  zinc  chloride  at  110°, 
it  is  converted  into  the  hydrochloride  of  apomorphine,  the 
formula  of  which  base  differs  from  that  of  the  parent  alkaloid  by 
the  elements  of  water,  though  its  formation  is  probably  attended 
by  polymerisation.  Apomorphine  may  be  obtained  in  a  state  of 
purity  by  dissolving  the  contents  of  the  tube  in  water,  adding 
excess  of  acid  carbonate  of  sodium,  and  agitating  with  ether  or 
chloroform,  in  either  of  which  apomorphine  is  freely  soluble 
(difference  from  morphine).  The  ethereal  solution  is  separated 
and  shaken  with  a  very  little  strong  hydrochloric  acid,  when 
crystals  of  the  hydrochloride  of  apomorphine  are  deposited.  These 
are  separated,  washed  with  a  little  cold  water,  and  purified  by 
recrystallisation.  From  its  aqueous  solution  of  the  hydrochloride, 
sodium  bicarbonate  precipitates  free  apomorphine  as  a  snow-white 
amorphous  substance,  readily  soluble  in  alcohol,  ether,  chloroform 
and  benzene,  which  speedily  turns  green  on  exposure  to  the  air. 
The  changed  alkaloid  is  partially  soluble  in  water  and  alcohol  with 
emerald-green  colour,  in  ether  with  magnificent  rose-purple,  and 
in  chloroform  with  fine  violet  tint.  The  colourless  solutions  of 
the  unchanged  substance  soon  acquire  these  tints.  In  its  physio- 
logical effects,  apomorphine  differs  from  morphine  in  a  very  marked 
manner,  being  a  prompt  and  non-irritant  emetic.      From  0*001 


320  APOMORPHINE. 

to  0*010  is  the  adult  medicinal  dose  by  the  stomach.  Dangerous 
and  even  fatal  symptoms  have  followed  the  hypodermic  injection 
of  0*012  gramme.  Apomorphine  gives  a  crimson-red  colour  with 
nitric  acid,  and  brown  with  iodic  acid,  but  (unlike  morphine)  yields 
a  rose-red  or  amethystine  colour  with  ferric  chloride,  changing  to 
violet  and  black.  The  most  delicate  reaction  of  apomorphine  is 
the  production  of  a  green  coloration  when  the  solution  is  ren- 
dered faintly  alkaline  with  potassium  hydrogen  carbonate  and 
exposed  to  the  air.  With  a  solution  containing  1  part  in  100,000, 
the  green  colour  appears  within  ten  minutes. 

Apomorphine  is  said  to  be  liable  to  be  formed  in  old  solutions 
of  morphine  hydrochloride,  which  consequently  acquire  emetic 
properties;  but  the  statement  is  disputed  by  Dott,  and  requires 
confirmation  (Pharm.  Jour.,  [3],  xvi.  287,  299,  604 ;  xvii.  80). 

Apomorphine  Hydrochloride,  C-^^jH.^>jN02^Cl,  forms  anhydrous, 
minute,  shining  crystals,  which  turn  greenish  on  exposure  to  light 
and  air.  It  is  freely  soluble  in  water  and  alcohol,  forming  a 
neutral  solution,  which  turns  green  on  boiling  or  standing,  and 
keeps  better  if  very  faintly  acid.  The  freshly-made  aqueous 
solution  should  be  colourless,  or  nearly  so.  It  is  generally  held 
that  if  a  1  per  cent,  solution  be  emerald-green,  the  sample  should 
be  rejected  for  medical  use;  but  D.  B.  Dott  (Pharm.  Jour.,  [3], 
xxi.  916)  has  pointed  out  that  the  coloration  is  so  intense  that 
very  little  actual  change  is  thereby  indicated.  Morrell  found  an 
old  solution  which  had  been  exposed  to  light  for  three  months  to 
act  quite  effectively.^ 

Basic  Associates  of  Morphine. 

As  already  stated,  opium  contains  a  large  number  of  bases,  some 
of  which  are  present  in  very  minute  amount,  or  are  altogether 
absent  from  some  samples.  The  names,  formulae,  solubilities,  and 
chief  colour-reactions  of  these  alkaloids  have  already  been  given 
(page  294  to  305),  and  morphine  has  been  described  at  length 
(page  309).  The  following  are  additional  facts  respecting  the 
less  important  bases  of  opium. 

CoDAMiNE,  CgongsNO^,  melts  at  126°  when  crystallised  from 
benzene,  and  121°  when  separated  from  alcohol  or  ether.  It  forms 
large  six-sided  prisms,  which  can  be  sublimed.  It  dissolves  moder- 
ately easily  in  hot  water,  giving  an  alkaline  solution.  Its  salts, 
which  are  amorphous,  give  precipitates  with  caustic  alkalies  and 

^Morrell  finds  that  a  patient  who  is  made  violently  ill  by  }  grain  of 
apomorphine  hydrochloride  administered  hypodermically,  can  take  |  grain 
thrice  daily  in  the  form  of  pills.  Apomorphine  acts  as  a  powerful  expectorant 
in  cases  of  chronic  bronchitis. 


CODEINE.  321 

ammonia,  soluble  in  excess  of  either  reagent  with  nitric  acid; 
codamine  gives  a  dark  green  coloration  with  sulphuric  acid,  and  in 
presence  of  a  minute  quantity  of  ferric  chloride  a  greenish  blue. 
For  other  colour-reactions  and  solubilities,  see  page  301  e^  seq. 

Codeine.  Codeia.  CigHgiNOg,  or  Ci^Hi^NOCOH^OCHg.  This 
base  has  the  constitution  of  a  morphine  methyl-ester.  The 
relation  of  codeine  to  morphine  and  synthesis  therefrom  are 
described  on  page  167.  Its  theoretical  relations  and  constitution 
have  been  recently  further  investigated  by  K  n  o  r  r  (Ber.,  xxii.  181, 
1113)  and  Skraup  and  Wiegmann  {Monatsch,  x.  732). 
Codeine  occurs  in  opium  in  proportions  ranging  from  0*1  to  1"0 
per  cent.-^ 

Codeine  crystallises  from  dry  ether  or  carbon  disulphide  in  smaU 
anhydrous  prisms.  From  water  it  is  deposited  in  weU-defined 
octohedra  or  orthorhombic  prisms  containing  1  aqua  and  melting 
under  boihng  water  to  an  oily  liquid.  Anhydrous  codeine  melts 
at  150°-155°,  and  solidifies  to  a  crystalhne  mass  on  cooling. 
Codeine  is  somewhat  soluble  in  water,  requiring  75  to  80  parts 
of  cold  water,  or  17  at  the  boiling-point.  It  is  readily  soluble  in 
alcohol,  ether,  amylic  alcohol,  chloroform  and  benzene,  but  is 
almost  insoluble  in  petroleum  spirit  (compare  page  301).  Codeine 
is  as  soluble  in  ammonia  as  in  water,  a  fact  utilised  to  separate  it 
from  morphine,  but  it  is  practically  insoluble  in  excess  of  caustic 
potash  or  soda,  and  is  precipitated  by  these  reagents  from  its 
aqueous  solution,  if  not  too  dilute.^  Solutions  of  codeine  are 
optically  active,  the  rotatory  power  being  much  affected  by  the 
nature  of  the  solvent,  and  the  presence  and  proportion  of  free  acid. 
In  alcoholic  solution  Sj  =  -136°;  in  chloroform,  -112°. 

Codeine  has  a  bitter  taste,  and  resembles  morphine  in  its  physio- 
logical action.  It  is  official  in  the  British  and  several  foreign 
Pharmacopoeias,  and  is  chiefly  employed  to  aUay  restlessness,  cough, 
and  other  symptoms  for  which  opium  is  generally  prescribed,  and 
when  the  latter  medicine  is  not  tolerated.  In  phthisis,  it  appears 
to  prevent  and  appease  the  tickling  irritation  of  the  cough,  with- 
out deranging  the  digestion.    It  is  an  important  remedy  in  diabetes, 

^  Codeine  is  usually  isolated  from  opium  by  precipitating  the  aqueous 
extract  by  calcium  chloride,  evaporating  and  cooling  the  filtrate,  redissolving 
the  deposited  crystals  of  the  hydrochlorides  in  water,  and  precipitating  the 
morphine  by  ammonia.  From  the  filtrate,  after  concentration,  the  codeine 
can  be  recovered  by  treating  by  precipitating  with  caustic  alkali,  and  purified 
by  crystallisation  from  ether. 

2  The  hydroxy  1-group  in  the  codeine  molecule  does  not  appear  to  be  phenolic, 
as  evidenced  by  the  insolubility  of  the  alkaloid  in  caustic  alkalies,  and  its 
negative  reaction  with  ferric  chloride. 

VOL.  III.  PART  II.  X 


322  DETECTION  OF   CODEINE. 

and  is  also  recommended  as  an  hypnotic  in  mental  disease.  The 
official  dose  is  from  J  to  2  grains.  In  larger  quantities,  codeine 
produces  narcotism,  often  preceded  by  vomiting  and  occasionally 
by  purging. 

Codeine  is  a  strong  base,  having  a  marked  alkaline  reaction,  and 
forming  crystallisable,  soluble  salts,  which  are  neutral  to  litmus  and 
methyl-orange.  The  free  base  precipitates  solutions  of  lead,  iron, 
copper,  and  certain  other  of  the  heavy  metals. 

Codeine  Hydrochloride  crystallises  in  radiated  groups  of  prisms 
containing  BHCl+SHgO,  soluble  in  about  20  parts  of  cold  water. 
The  solution  is  Isevo-rotatory  (Sj=  —108°).  The  crystals  lose  a 
portion  of  their  water  (J  aqua)  readily,  but  the  remainder  is  only 
driven  off  by  many  days  heating  at  100°  (Schmidt,  Pharm. 
Jour.,  [3],  xxi.  82),  but  easily  at  120°  (Dott).  Hence  the  pro- 
portion of  water  in  commercial  samples  of  the  salt  is  variable. 

Codeine  Phosphates.  The  salt  BH3PO4-I-2H2O  is  obtained  as  a 
crystalline  precipitate  by  adding  codeine  to  a  solution  of  phosphoric 
acid  till  the  reaction  is  only  faintly  acid,  and  then  adding  excess 
of  alcohol.  When  recrystallised  from  water  the  composition  is 
unchanged,  but  the  salt  deposited  from  the  solution  in  hot  dilute 
alcohol  contains  2BH3PO4+H2O.  Both  forms  lose  their  water  at 
100°,  and  are  met  with  in  commerce,  as  also  a  preparation  contain- 
ing excess  of  phosphoric  acid.  The  usual  composition  of  com- 
mercial codeine  phosphate  is  B2H3PO4 -|- HgO  (Dott).  If  the 
salt  turn  grey  or  yellow  at  100°,  the  presence  of  impurity  is 
indicated.  The  phosphate  is  said  to  be  the  preferable  form  of 
employing  codeine  for  hypodermic  injections. 

Detection  and  Determination  of  Codeine. 

In  its  reactions  and  general  characters  codeine  presents  a  strong 
resemblance  to  morphine,  but  is  sharply  distinguished  by  its  ready 
solubility  in  ether  and  chloroform,  and  its  precipitation  by  excess 
of  caustic  alkali.  Codeine  does  not  reduce  iodic  acid,  and  gives  no 
coloration  with  ferric  chloride.  In  strong  nitric  acid  it  dissolves 
to  a  yellow  liquid  which  should  not  become  red  (difference  from  and 
absence  of  morphine).  With  pure  sulphuric  acid,  codeine  gives  no 
coloration,  but  on  warming,  or  very  prolonged  standing  (several 
days)  at  the  ordinary  temperature,  a  blue  colour  is  developed.  This 
colour  is  produced  if  a  trace  of  nitric  acid,  ferric  chloride,  or  other 
oxidising  agent  be  present,  an  arseniate  being  the  preferable  reagent. 
The  blue  coloration  on  warming  with  sulphuric  acid  and  ferric  chloride 
is  apparently  common  to  all  ethers  of  the  codeine  class.  Frdhde's 
reagent  (page  147)  is  stated  by  some  observers  to  produce  a  dirty 
green  colour,  soon  becoming  deep  blue,  and  changing  in  twenty-four 
hours  to  yellow ;  according  to  others,  a  cherry-red  tint,  changing 


DETERMINATION  OF   CODEINE.  323 

to  violet,  is  produced.  L.  R  a  b  y  states  that  if  solid  codeine  be 
stirred  up  with  two  drops  of  a  solution  of  sodium  hypochlorite, 
four  drops  of  strong  sulphuric  acid  added,  and  the  whole  mixed 
together,  a  splendid  and  persistent  blue  coloration  results.  Esculin 
was  the  only  other  substance  (of  thirty  examined)  which  gave  at 
all  a  similar  reaction.  L  a  f  o  n  uses  a  solution  of  1  gramme  of 
ammonium  selenite  in  20  c.c.  of  strong  sulphuric  acid,  which  gives 
a  magnificent  green  colour  with  traces  of  codeine.  Other  reactions 
are  given  on  pages  302  to  306. 

Commercial  codeine  has  been  met  with  adulterated  with  ammo- 
nium tartrate  {Pharm.  Jour.^  [3],  xiv.  1035),  which  salt  closely 
resembles  it,  but  is  distinguished  from  codeine  by  its  insolubility 
in  alcohol. 

Claassen  has  based  a  method  of  determining  codeine  on  the 
well-known  fact  that  it  completely  decomposes  morphine  salts  {N.Y. 
Pharm.  Rundschau^  1890,  40  ;  Jour.  Chem.  Sac,  Iviii.  1198).  The 
warm  aqueous  solution  of  the  free  base  is  treated  with  excess  of 
morphine  sulphate  with  frequent  shaking,  and  allowed  to  stand  ia 
the  cold  for  at  least  twenty-four  hours,  when  the  deposited  morphine 
is  filtered  ofi',  dried,  and  weighed  (or  titrated).  The  amount  found, 
multiplied  by  0*9868,represents  the  anhydrous  codeine,  or  by  1  "041 2, 
the  hydrated  codeine  (CigHgiNOg  +  HgO).  To  separate  morphine 
and  codeine,  the  mixed  bases,  or  their  salts,  are  evaporated  to  dry- 
ness with  excess  of  magnesia.  The  residue  treated  with  water, 
and  the  liquid  shaken  repeatedly  with  ether  free  from  alcohol,  the 
ether  distilled  off,  and  the  residue  exhausted  with  hot  water.  In 
the  resultant  solution  the  codeine  can  be  determined  as  above 
described. 

Claassen  (loc.  cit)  has  also  pointed  out  that  free  codeine  com- 
pletely decomposes  ammonium  salts  when  heated  with  them,  and 
has  based  on  the  fact  a  method  of  determining  the  alkaloid ;  but 
as  morphine  behaves  in  a  similar  manner,  the  fact  has  little  practical 
value. 

The  simplest  means  of  determining  codeine  and  morphine  in 
admixture  is  to  precipitate  the  solution  of  the  hydrochlorides  with 
acid  carbonate  of  sodium,  and  wash  the  dried  precipitate  with 
chloroform.  The  residue  consists  of  morphine.  The  aqueous 
filtrate  is  treated  with  caustic  soda,  agitated  several  times  with 
chloroform,  the  various  chloroform  washings  and  extracts  united, 
evaporated,  and  the  residual  codeine  dried  at  110°,  and  weighed 
(D.  B.  Dott). 

Pseudocodeine,  C;^8H2iN03-f-H20,  was  discovered  by  E.  Merck 
in  preparing  apocodeine  {Arch.  Pharm.,  ccxxix.  161).  It  is  a 
strong  base,  crystallising  in  needles  melting  at  178°-180°.     It  is 


324  APOCODEINE.      CRYPTOPINfi, 

Isevo-rotatory,  forms  crystallisable  salts,  gives  no  reaction  with  ferric 
chloride,  and  has  a  physiological  action  similar  to,  but  weaker  than, 
that  of  codeine. 

Apocodeine,  CigHiglSrOg,  is  said  to  be  produced  by  heating  codeine 
hydrochloride  with  a  concentrated  solution  of  zinc  chloride  for 
fifteen  minutes.  It  is  described  as  gummy,  insoluble  in  water, 
soluble  in  alcohol  and  ether,  and  yielding  amorphous  salts.  In 
physiological  action  it  is  a  valuable  expectorant  and  mild  emetic. 
Apocodeine  gives  a  characteristic  blood-red  colour  with  nitric  acid. 
D.  B.  D  0 1 1  doubts  the  existence  of  apocodeine,  and  states  that 
commercial  apocodeine  hydrochloride  is  not  of  a  very  definite 
nature,  being  probably  a  mixture  of  an  amorphous  modification 
of  codeine,  polymerised  bases,  chlorocodide,  and  apomorphine.  The 
physiological  results  appear  to  harmonise  with  this  view  {Fharm. 
Jour.,  [3],  xxi.  878,  916,  955,  996). 

Methocodeine  or  Dimethylmorphine,  C-^*j'E.^^1^0{0CK^2^  is  of 
interest  merely  from  its  theoretical  relation  to  morphine,  codeine 
and  thebaine  (compare  page  296).  It  is  a  base  forming  hard  bril- 
liant lamiuEe  melting  at  119°,  and  yields  with  sulphuric  acid  a 
brown  coloration,  turning  violet  on  addition  of  water. 

Cryptopine,  C21H23NO3,  occurs  in  but  very  small  quantity  in 
opium,  and  is  precipitated  on  adding  caustic  soda  to  the  mother- 
liquor  from  which  codeine,  narceine,  thebaine  and  papaverine  have 
been  separated.  It  crystallises  from  alcohol  in  minute  six-sided 
prisms.  It  is  optically  inactive,  sparingly  soluble  in  boiling  alcohol, 
very  slightly  in  benzene  or  petroleum  spirit,  but  more  readily  in 
chloroform.  When  freshly  precipitated  it  is  soluble  in  ether,  but 
slowly  separates  from  the  solution.  (See  also  pages  301,  304.) 
Cryptopine  and  its  salts  have  a  bitter  taste,  and  pungent  cooling 
after-taste  ;  they  are  hypnotic  and  mydriatic. 

Cryptopine  salts  when  dissolved  in  hot  water  usually  produce  on 
cooling  a  gelatinous  mass,  which  is  gradually  changed  to  crystals. 
The  normal  mlphate  does  not  crystallise ;  the  acid  salt  gelatinises, 
as  the  solution  cools,  and  the  jelly  shows  but  slight  signs  of  crystal- 
lising, even  after  standing  several  weeks.  The  acid  oxalate  and 
acid  tartrate  are  very  sparingly  soluble.  Neutral  cryptopine  meco- 
nate,  {C^^^^O^^C^'Rfi^-\-lOB.cfi,  is  insoluble  in  cold,  and  but 
slightly  soluble  in  boiling  water,  and  is  probably  the  form  in  which 
the  alkaloid  exists  in  opium  {Pharin.  Jour.,  [3],  xviii.  250). 

Deuteropine,  C20H21NO5,  an  alleged  homologue  of  protopine 
and  cryptopine,  requires  further  examination. 

Gnoscopine,  C34H3gN20ip  occurs  in  the  mother-liquors  of 
narceine.  When  recrystallised  from  boiling  spirit  the  base  forms 
long,  thin,  white  needles,  having  a  woolly  appearance  when  dried. 


LANTHOPIKE.      LAUDANINE.  326 

It  melts  at  233°,  decomposing  at  the  same  time,  and  burns  with  a 
smoky  flame,  leaving  a  skeleton  of  charcoal.  In  pure  sulphuric 
acid,  gnoscopine  dissolves  with  slightly  yellow  colour,  which 
becomes  at  once  carmine-red  upon  addition  of  a  trace  of  nitric  acid, 
the  colour  being  permanent.  This  reaction  distinguishes  the  base 
from  rhoeadine,  which  becomes  red  with  sulphuric  or  hydrochloric 
acid  alone  (Fharm.  Jour.,  [3],  ix.  82).  Gnoscopine  hydrochloride 
gives  a  buff-coloured  precipitate  with  platinic  chloride.  (See  also 
page  301.) 

Hydrocotarnine,  C12H15NO3,  is  formed  from  narcotine,  together 
with  meconin,  by  the  action  of  nascent  hydrogen.  It  volatilises 
partly  unchanged  at  100°,  and  forms  readily  soluble  salts. 

Lanthopine,  CggHggXO^,  is  obtained  from  the  mother-liquors 
left  from  the  preparation  of  morphine  by  the  Kobertson-Gregory 
process  (see  page  308).  It  is  a  weak  base  forming  no  acetate.  It 
is  coloured  orange-red  by  nitric  acid,  and  pale  violet  by  sulphuric 
acid,  the  latter  colour  changing  to  a  dark  brown  on  heating.  (See 
also  pages  301,  304.) 

Laudanine,  C20II25NO4,  occurs  with  lanthopine.  It  has  re- 
cently been  prepared  on  a  commercial  scale  by  Merck  from 
opium  mother-liquors,  but  the  yield  is  only  one-third  that  of 
cryptopine.  Laudanine  crystallises  from  its  solution  in  boiling 
alcohol  in  transparent  granules  or  hexagonal  prisms  melting  at  166°. 
Laudanine  is  l8evo-rotatory,tasteless,  and  poisonous,  the  hydrochloride 
being  bitter  and  resembling  strychnine  in  its  effects.  It  resembles 
morphine  in  dissolving  in  caustic  alkali  solutions,  but  the  sodium- 
derivative  is  reprecipitated  in  glistening  white  needles  on  adding 
excess  of  caustic  alkali.  From  its  solution  in  caustic  alkali  lauda- 
nine is  wholly  unremoved  by  chloroform  or  amylic  alcohol,  but  is 
extracted  if  precipitated  by  ammonia.  Its  phenolic  character  is 
further  evidenced  by  the  green  coloration  yielded  with  ferric 
chloride.  Treatment  with  methyl  iodide  converts  laudanine  into 
a  base  chemically  resembling  codeine,  and  distinct  from  laudano- 
sine.  The  solution  of  laudanine  in  pure  concentrated  sulphuric 
acid  has  only  a  very  faint  pink  tint ;  the  same  acid  containing  iron 
yields  a  slightly  deeper  tint ;  but  on  heating  either  solution  till 
the  acid  begins  to  volatilise,  a  violet  coloration  is  obtained.  With 
nitric  acid,  laudanine  gives  an  orange-red  colour.  Laudanine  is  a 
strong  base,  having  an  alkaline  reaction,  and  forms  well-crystal- 
lised salts  of  a  bitter  taste.  BHI  is  sparingly  soluble  in  cold 
water,  and  BHCl  easily  soluble  in  water,  but  nearly  insoluble  in 
brine.     (See  also  pages  301,  304.) 

Laudanosine,  C21H27NO4,  is  homologous  with  laudanine,  but  is 
not  produced  by  heating  that  base  with  methyl  iodide.     Laudano- 


326  MECOlirrDINE.      NARCEINE. 

sine  is  isolated  by  conversion  into  its  sparingly  soluble  hydriodide. 
[t  crystallises  from  benzene  in  needles  melting  at  91''.  Both  the 
free  alkaloid  and  its  salts  taste  very  bitter,  and  are  tetanic  poisons. 
Laudanosine  is  dextro-rotatory.  The  solution  is  strongly  alkaline.  It 
gives  no  coloration  with  ferric  chloride.     (See  also  pages  301,  304.) 

Morphine,  CiyH^gNOg,  has  already  been  fully  described  (page 
309). 

Meconidine,  C21H23NO4  (page  301),  forms  a  brownish  yellow 
amorphous  mass,  soluble  with  difficulty  in  ammonia,  but  readily  in 
caustic  alkalies.  The  base  cannot  be  removed  from  its  solution  in 
caustic  soda  by  agitation  with  ether,  but  is  extracted  from  its 
ammoniacal  and  lime-water  solutions.  Meconidine  is  alkaline  in 
reaction,  and  nearly  destitute  of  taste ;  but  yields  very  bitter, 
unstable  salts.  It  is  very  easily  decomposed  by  mineral  acids,  with 
production  of  a  rose  coloration.  It  is  dissolved  by  strong  sulphuric 
acid  with  an  olive-green,  and  by  nitric  acid  witli  an  orange-red  colour. 

Narceine.  C23H29NO9;  or  Ci3H2oN04.CO.C6H2(OCH3)2.COOH 
(compare  page  299).  This  base  was  originally  discovered  by 
Pe  lie  tier,  who  attributed  to  it  the  melting-point  92°  C,  but 
Hess  e  found  it  to  melt  at  1 45"".  This  latter  figure,  although  sub- 
sequently corrected  by  Hesse  himself,  has  been  generally  adopted 
by  compilers,  though  Glaus  and  M  e  i  x  n  e  r  found  162°;  but  E. 
Merck  has  shown  {CJiem.  Zeit.,  1889,  p.  525)  that  the  ordinary 
commercial  alkaloid  of  English  manufacture  melts  between  150° 
and  160°,  and  the  pure  base  at  170°-171°.^  JSFarceine  crystallises 
from  water  in  long  white  prisms  or  delicate  needles,  containing  2H2O, 
which  is  driven  off  at  100°.  It  has  a  bitter  taste,  with  styptic 
after-taste,  and  powerful  hypnotic  properties.  It  is  optically 
inactive.  It  is  very  sparingly  soluble  in  cold  water  or  spirit,  but 
dissolves  very  easily  on  heating.  It  is  but  slightly  soluble  in  chloro- 
form, and  insoluble  in  ether  and  benzene.  Narceine  is  precipitated 
on  adding  ammonia  or  caustic  potash  to  solutions  of  its  salts,  but 
dissolves  in  excess  of  either  reagent,  and  on  addition  of  a  large 
excess  of  caustic  alkali  is  reprecipitated  as  an  oily  liquid.^ 

Narceine  is  a  very  weak  base,  the  free  alkaloid  having  a  very 
feeble  alkaline  reaction  to  delicate  litmus ;  the  solutions  of  its  salts 
may  be  titrated  with  litmus  just  as  if  the  alkaloid  were  absent.  The 
acetate  is  decomposed  by  water,  and  the  base  is  said  to  be  extracted 
by  chloroform  (but  not  by  amylic  alcohol)  from  liquids  containing 

1  D  o  1 1  states  that  the  meltiDg-point  is  indefinite,  as  partial  decomposition 
occurs. 

^  Narceine  containing  a  carboxyl-group,  its  solubility  in  alkalies  is  normal, 
but  it  seems  probable  that  the  oil  precipitated  by  excess  of  caustic  alkali  is  an 
alkaline  narceinate  rather  than  the  free  alkaloid. 


NARCEINE.      NARCOTINE.  32T 

even  free  mineral  acids.  BHCl  forms  needles  or  sliort  stout 
prisms  very  easily  soluble  in  water  and  alcohol,  and  melting  with 
decomposition  at  163°.  Narceine  liberated  from  the  hydrochloride 
or  other  salts  by  ammonia  retains  hydrochloric  acid  with  great 
persistency,  and  cannot  be  purified  by  recrystallisation  from  water 
or  dilute  alcohol.  According  to  E.  Merck  (Ghem.  Zeit,  1889, 
p.  525 ;  Pharm.  Jour.,  [3],  xix.  1034;  xx.  481)  narceine  can  best 
be  obtained  pure  by  crystallisation  from  water  containing  some 
ammonia  or  caustic  alkali,  but  a  considerable  quantity  remains  in 
permanent  solution.  For  therapeutic  purposes,  the  presence  of  a 
small  proportion  of  hydrochloride  is  of  no  consequence,  and 
Merck  considers  that  a  preparation  free  from  meconin,  and  so  far 
freed  from  basic  salt  as  not  to  melt  below  165°,  is  sufficiently  pure. 

Chlorine-water,  followed  by  ammonia,  gives  a  blood-red  colour 
with  narceine,  but  many  other  substances  (e.g.,  tannin)  behave 
similarly.  Potassium  bichromate  gives  a  crystalline  precipitate 
after  some  time.  Iodine  gives  a  brown  precipitate  in  narceine 
solutions,  but  if  ammonia  be  added  to  remove  excess  of  iodine  the 
precipitate  is  seen  to  be  blue.  Weak  iodine  solution  colours  nar- 
ceine black-blue ;  in  boiling  water  a  colouiless  solution  is  obtained, 
but  the  crystals  formed  on  cooling  have  a  violet  or  blue  colour. 
Sulphuric  acid  containing  iodic  acid  gives  with  narceine  a  black 
coloration  changing  to  red  (see  also  page  302  e^  seq.). 

''Meconarcein e,"  according  to  E.  M e r c k,  is  a  preparation 
of  a  very  variable  character,  of  which  one  form  consists  of  a  yel- 
lowish liquid  containing  codeine,  narceine,  and  an  unidentified  acid 
soluble  in  ether,  but  no  meconic  acid.  In  another  case  the  "  meco- 
narceine"  formed  a  white  powder  melting  at  110°,  and  consisting 
of  a  mechanical  mixture  of  narceine  and  meconic  acid,  which  on 
adding  water  combine  chemically,  and  the  recrystallised  products 
melt  with  evolution  of  gas  at  126°,  which  is  the  melting-point  of 
acid  narceine  meconate  (Pharm.  Zeit.,  1889,  p.  90). 

Narootine,  CggHggNOy,  occurs  in  opium  in  very  variable 
quantity,  the  usual  range  being  from  1*3  to  nearly  11  per  cent.; 
but  some  samples  contain  traces  too  minute  to  be  recognised  by 
the  usual  methods.  Narcotine  may  be  extracted  from  dried  opium 
by  ether  or  benzene,  or  by  the  same  solvents  from  the  precipitate 
produced  by  ammonia  in  the  aqueous  solution  of  opium.  ^  It  may 
be  separated  from  narceine  by  precipitating  the  solution  with 
excess  of  ammonia,  when  the  narceine  remains  in  solution. 

Narcotine  crystallises  from  alcohol  or  ether  in  colourless,  trans- 
parent, glittering  prisms  or  groups  of  needles,  which  melt  at  170°, 

^  Opium  from  which  the  narcotine  has  been  removed  in  this  manner  is  now 
an  article  of  commerce. 


328  REACTIONS   OF  NARCOTINE. 

and  resolidify  at  130°,  crystallising  if  cooled  slowly.  Above  200' 
narcotine  is  decomposed  into  m  e  c  o  n  i  n  and  cot  a  mine. ^  It  is 
feebly  narcotic,  exhibiting  poisonous  eifects  only  in  somewhat  large 
doses  (rS  to  3'0  grammes).  The  solid  base  is  nearly  tasteless, 
but  the  solutions  are  bitter.  In  the  free  state  narcotine  is  Isevo- 
rotatory,  but  the  salts  exhibit  dextro-rotation.^ 

D.  B.  D  0 1 1  has  obtained  the  acetate,  sulphate  and  hydrochloride 
of  narcotine  in  a  crystalline  state ;  but  the  first  of  these  salts  is  almost 
completely  decomposed  by  solution,  the  base  being  precipitated 
and  free  acetic  acid  formed.  The  same  reaction  occurs  when 
sodium  acetate  is  added  to  a  solution  of  narcotine  hydrochloride 
(compare  page  306).  The  hydrochloride  and  sulphate  of  narcotine 
are  somewhat  more  stable,  their  solutions  remaining  clear  even 
when  largely  diluted ;  but  they  react  with  litmus  just  as  if  the 
acid  were  uncombined,^  and  yield  the  narcotine  to  chloroform 
and  similar  solvents.  These  facts  prove  the  basic  properties  of 
narcotine  to  be  very  feebly  marked. 

Narcotine  meconate  forms  a  syrupy  solution,  which  on  evapora- 
tion dries  to  a  varnish  which  redissolves  perfectly  in  water. 

The  caustic  alkalies,  alkali-metal  carbonates,  and  ammonia  throw 
down  narcotine  as  a  white  crystalline  precipitate,  almost  insoluble 
in  cold  water  and  in  excess  of  the  precipitants.  It  may  be  extracted 
from  the  alkaline  liquid  by  chloroform  or  benzene,  or  less  readily 
by  ether  or  amy  lie  alcohol.  It  is  practically  unaffected  by  petroleum 
spirit  (compare  page  301). 

]N"arcotine  is  precipitated  by  the  usual  alkaloidal  reagents,  but  the 
reactions  are  not  very  characteristic.  With  potassium  thiocyanate 
it  yields  a  crystalline  precipitate  readily  soluble  in  acids,  even  in 
acetic  acid.  Iodised  potassium  iodide  precipitates  narcotine  from 
extremely  dilute  solutions.  Narcotine  may  be  precipitated  and 
titrated  by  Mayer's  solution  (page  139). 

If  a  solution  of  narcotine  in  dilute  hydrochloric  acid  be  treated 
with  bromine,  a  yellow  precipitate  is  obtained,  which  dissolves  on 
boiling ;  by  gradually  adding  bromine-water,  and  boiling,  a  fine  rose 

^  The  constitution  and  decomposition-products  of  narcotine  are  described  on 
page  298. 


2  Hesse  found  for  the  free  alkaloid — 


Chloroform  and 


Alcohol.  Alcohol,  Chloroform. 

Concentration,    .       ,  074  2  2  and  6 

Sd,        .        .        .        .      -185°-0  -191' -5  -207-8 

For  a  solution  in  * '  benzine  "  Dott  and  Peddie  found  Sd  =  -  229°  (when  c 
was  1  '5),  and  for  a  solution  in  dilute  oxalic  acid,  S©  —  -*-  62°. 
'  Narcotine  hydrochloride  is  neutral  to  methyl-orange  (Dot t). 


OXYNARCOTINE.      PAPAVERINE.  329 

colour  is  produced,  but  is  readily  destroyed  by  excess  of  bromime. 
The  reaction  is  characteristic.  With  chlorine-water,  narcotine  gives 
a  yellowish  green  colour,  turned  orange  by  ammonia.  Iodic  acid 
gives  no  coloration  with  narcotine.  If  narcotine  be  mixed  with 
twice  its  weight  of  cane-sugar,  and  the  mixture  moistened  with 
strong  sulphuric  acid,  a  fine  and  persistent  mahogany-brown  colora- 
tion is  produced,  said  by  M.  R  o  b  i  n  to  be  highly  characteristic. 
{See  also  page  302.) 

Opianine,  to  which  the  formula  CgiHgiNOy  is  attributed,  ia 
probably  merely  impure  narcotine. 

OxYNARCOTiNE,  CggHggNOg,  is  Contained  in  the  mother-liquors 
of  narcotine.^  It  forms  minute  crystals,  somewhat  soluble  in  hot 
water,  but  little  soluble  in  hot  alcohol,  and  insoluble  in  ether, 
chloroform  or  benzene.  By  oxidation  with  ferric  chloride  it  yields 
cotarnine  and  hemipinic  acid.  BHCl-t-2H20  forms 
crystals.     (See  also  page  101.) 

Papaverine,  CgoHgiNO^,  is  a  weak  base  of  feeble  narcotic  pro- 
perties. It  is  separated  from  narcotine  by  crystallisation  from  a 
strong  solution  in  oxalic  acid,  the  acid  oxalate  of  papaverine  being 
very  sparingly  soluble.  Papaverine  crystallises  in  rhombic  prisms 
or  needles,  or  sometimes  in  scales.  It  is  sliglitly  laavo-rotatory,  ^ 
though  its  hydrochloride  is  inactive.  The  neutral  sxtccinate  forms 
large  tabular  crystals  melting  at  171°,  and  soluble  in  hot  water; 
the  benzoate,  triclinic  crystals  melting  at  145°,  and  soluble  in 
alcohol  but  insoluble  in  water;  and  the  salicylate,  monoclinic 
crystals  melting  at  130°.  Sulphuric  acid  containing  iodic  acid 
gives  with  papaverine  a  purple  colour,  turning  black  and  green. 
Dilute  solutions  of  papaverine  salts  are  not  precipitated  by  phospho- 
molybdic  acid.  Tincture  of  iodine,  added  to  an  alcoholic  solution 
of  papaverine,  gives  gradually  a  precipitate  of  crystalline  nciedles. 
With  potassio-iodide  of  cadmium,  papaverine  yields  a  dense  white 
precipitate.     (See  also  page  301  e^  seq.) 

Papaverosine,  found  by  Deschamps  (1864)  in  the  dried  seed 
capsules  of  the  poppy,  crystallised  in  prisms,  was  soluble  in  alcohol, 
ether,  chloroform  and  benzene,  and  formed  a  gummy  hydrochloride. 
With  sulphuric  acid  it  gave  a  violet  coloration. 

*  Oxynarcotine  was  first  isolated  in  an  impure  condition  by  D.  Brown, 
from  crude  narceine.  This  product  was  purified  and  analysed  by  Alder 
Wright  and  Beckett. 

2  G.  Goldschmidt  {Monatsch,  ix.  42)  states  that  pure  papaverine  is  inac- 
tive, and  suggests  that  the  optical  activity  of  laudanine  should  be  reinvesti- 
gated, as  these  two  alkaloids  constitute  the  only  two  known  exceptions  to  the 
Bel-Van't  Hoff  theory  that  derivatives  of  optically  active  substances  are  also 
active. 


SIO  PROTOPINE.      PSEUDOMOEPHINE. 

PoRPHYROXiNB,  described  by  Merck  in  1837  as  the  red  colour-^ 
ing  matter  of  opium,  according  to  Hesse  is  a  mixture  of  several 
bases,  one  of  which  is  meconidine,  and  another  probably 
r  h  08  a  d  i  n  e,  which  latter  alkaloid  also  occurs  in  the  capsules  and 
other  parts  of  the  red  poppy.  Kanny  Lall  Dey  {Pharm. 
Jour.,  [3],  xii.  397)  states  that  by  treating  the  aqueous  extract  of 
Indian  opium  with  ammonia  or  sodium  carbonate,  and  immediately 
agitating  with  ether,  the  ethereal  solution  always  leaves  on  evapora- 
tion a  body  (rhoeadine  ?)  which,  when  warmed  with  dilute  hydro- 
chloric acid,  gives  a  rich  purple  coloration,  and  he  recommends  the 
reaction  as  a  test  for  Indian  opium.^  With  Turkey  and  Smyrna 
opium  no  such  reaction  is  obtained. 

Protopine,  C20H19NO5,  appears  to  be  the  most  widely-distributed 
of  all  the  opium  alkaloids.  It  is  found  in  very  minute  quantity  in 
opium,  but  has  been  met  with  also  in  Macleya  cordata,  Stylo- 
yhorum  dijphyllum^  Sanguinaria  Canadensis,  and  CheUdonium 
majus.  Protopine  resembles  cryptopine,  but  the  solutions  of  its 
salts  have  a  bitter  taste,  and  do  not  gelatinise  on  cooling.  In 
small  doses,  protopine  acts  on  frogs  as  a  narcotic,  and  in  stronger 
doses  paralyses  the  muscle-substance,  and  the  peripheral  ends  of 
the  nerves.  Upon  mammals  it  has  a  poisonous  action  like  that  of 
camphor,  but  differs  from  it  in  paralysing  the  circulating  organs. 
(See  also  pages  301,  304.) 

PsBUDOMORPHiNE.  Oxydimorphiue.  Cg^HggNgOg.^  This  alkaloid 
is  best  purified  by  solution  in  ammonia,  from  which  it  crystallises 
in  colourless  crusts  or  delicate  silky  needles  containing  3  aqua.  It 
is  a  very  weak  base,  forming  no  acetate,  and  is  without  action  on 
vegetable  colours.  It  is  tasteless  and  not  poisonous.  It  dissolves 
readily  in  caustic  alkalies  and  milk  of  lime,  but  is  insoluble  in  all 
the  ordinary  alcoholic  and  ethereal  solvents,  as  also  in  dilute 
sulphuric  acid  and  alkaline  carbonates.  (Compare  page  301.)  Its 
most  soluble  salt  is  the  hydrochloride,  which  requires  70  parts  of 
cold  water  for  solution.  On  adding  ammonia,  avoiding  excess,  the 
alkaloid  is  precipitated  in  a  crystalline  state  from  the  hot,  and  in  a 
gelatinous  state  from  the  cold  solution.  Hesse  finds  that  when 
pseudomorphine  is  mixed  with  an  equal  weight  of  cane-sugar,  and 

1  Merck  repeatedly  dips  a  slip  of  filter-paper  in  the  ethereal  solution, 
allowing  it  to  dry  spontaneously  after  each  immersion.  The  paper  is  then 
moistened  with  hydrochloric  acid  and  exposed  to  steam,  when  it  will  acquire, 
especially  after  drying,  a  more  or  less  distinct  rose-red  colour. 

2  Pseudomorphine  occurs  very  rarely,  having  been  observed  by  Hesse  in 
good  Smyrna  opium  only  once  in  four  years.  It  may  be  prepared  by  treating 
morphine  with  oxidising  agents  of  moderate  power,  such  as  potassium  ferri- 
cyanide  or  dilute  permanganate  (page  144). 


RHCEADINE.      THEBAINE.  331 

strong  sulphiiric  acid  (pure)  added,  a  characteristic  dark  green 
coloration  is  obtained,  which  gradually  turns  brown  (compare  test  5, 
page  315).  If  the  acid  contain  a  minute  quantity  of  iron,  a  blue 
coloration  changing  to  green  is  produced. 

Rhceadine,  CgiHgjKOg,  exists  in  all  parts  of  the  red  poppy 
(Papaver  Bhoeas),  and  in  the  ripe  seed-capsules  of  the  white  poppy. 
It  forms  small  white  prisms,  which  are  tasteless  and  not  poisonous. 
Its  solutions  in  weak  acids,  avoiding  excess,  are  colourless,  but  on 
adding  excess  of  sulphuric  or  strong  hydrochloric  acid  a  purple-red 
colour  is  produced.  This  is  destroyed  by  alkalies  and  restored  by 
acids,  and  is  so  intense  that  1  part  of  rhoeadine  will  colour  10,000 
parts  of  water  purple-red,  200,000  deep  rose-red,  and  800,000 
distinctly  red,  although  only  a  fraction  of  the  base  is  converted 
into  colouring  matter.  The  colourless  solution  of  rhoeadine  in 
acids  is  precipitated  by  tannin.  On  adding  potassium  iodide  ta 
a  solution  of  the  acetate,  the  hydriodide  is  precipitated  as  a  dense 
crystalline  mass,  consisting  of  microscopic  prisms.  An  aqueous 
solution  of  rhoeadine  becomes  red  by  prolonged  boiling,  part  of  the 
alkaloid  being  converted  into  the  isomeric  base  rhoeagenine 
(soluble  without  colour  in  acids),  and  on  adding  a  drop  of  hydro- 
chloric or  sulphuric  acid  the  whole  base  is  decomposed,  the 
solution  acquiring  a  purple-red  colour.  Cold  dilute  sulphuric  acid 
converts  solid  rhoeadine  into  a  colourless  resinous  mass,  which  soon 
dissolves  with  splendid  purple  colour,  changing  to  dark  purple  on 
boiling,  and  depositing  on  cooling  small  prisms  which  are  brownish 
red  by  transmitted  and  green  by  reflected  light ;  while  the  liquid 
retains  rhoeagenine  equal  to  99  per  cent,  of  the  rhoeadine  present, 
together  with  the  colouring  matter. 

Opium  sometimes  contains  a  base  which  gives  the  above  colour- 
reactions  with  sulphuric  acid,  but  it  is  somewhat  doubtful  if  it  is 
actually  rhoeadine.      (Compare  Porphyroxine,  page  330.) 

Thebaine,  C19H21NO3,  or  01^1115X0(0.0113)2.  Thebaine  occurs 
in  opium  in  proportions  ranging  from  0"15  to  I'O  per  cent.  It 
crystallises  in  silvery  scales  from  dilute  alcohol,  and  in  needles  or 
hard  quadratic  prisms  from  strong  alcohol.  Thebaine  melts  at 
193°,  and  is  not  sublimable.^  It  has  a  sharp  and  styptic  taste, 
and  is  a  powerful  tetanic  poison,  producing  symptoms  resembling 
those  due  to  strychnine.  The  fatal  dose  is  smaller  than  that  of 
morphine.    Thebaine  gives  a  reddish  brown  coloration  with  chlorine- 


1  This  is  Hesse's  experience,  and  is  confirmed  by  Dott.  According  to  other 
observers,  at  about  135°  it  sublimes  without  fusing,  and  is  deposited  in  minute 
crystals  resembling  caflFeine  ;  while  at  higher  temperatures,  needles,  cubes,  and 
prisms  are  obtained. 


332  THEBAINE.      TRITOPINE. 

water  and  ammonia.  Its  other  colour-reactions  (and  its  solubilities) 
have  already  been  described.     (See  page  301  e^  seq.) 

Thebaine  is  stated  to  be  extracted  (with  some  difficulty)  by 
chloroform  from  its  acid  solutions  ;  but  the  statement  requires  con- 
firmation, as  it  is  inconsistent  with  the  strongly-marked  basic 
characters  of  thebaine.^  From  narcotine,  thebaine  may  be  separated 
by  treating  the  concentrated  acetic  solution  with  excess  of  basic 
lead  acetate,  which  precipitates  the  narcotine  only.  Dilute  acids 
readily  alter  thebaine,  converting  it  into  the  isomeric  bases 
thebenine  and  thebaicine,  which  are  sparingly  soluble  in 
hot  alcohol  and  insoluble  in  other  simple  solvents.  When  heated  to 
90°,  under  pressure,  with  fuming  hydrochloric  acid,  thebaine  yields 
a  base  having  the  probable  formula  C^,jE.^^0{0}l)2,  called  by  its 
discoverer,  W.C.  Howard  {Ber.,  xvii.  527;  xix.  1596)  m  o  r  p  h  o- 
thebaine,  to  indicate  its  origin  and  relation  to  morphine. 

Tkitopine,  04211^4^2^7'  "^^^  isolatcd  by  Kauder  in  minute 
quantity  from  the  mother-liquors  of  the  opium-alkaloid  manufac- 
ture. It  resembles  morphine  and  laudanine  in  being  soluble  in 
soda  solution,  but  is  reprecipitated  in  the  form  of  an  oil  by  a  large 
excess  of  the  reagent.  Tritopine  crystallises  in  characteristic 
anhydrous,  transparent,  needle-like  plates  melting  at  182°,  easily 
soluble  in  chloroform,  but  only  slightly  in  ether.  With  sulphuric 
acid  it  behaves  like  laudanine.  It  appears  to  be  a  di-acid  base 
{Arch.  Pharm.y  ccxxviii.  419). 

Opium. 

Opium  is  a  gummy  mass,  consisting  of  the  inspissated  juice 
from  the  incised  unripe  fruit-capsules  of  Papaver  somniferum, 
hardened  in  the  air. 

Opium  is  produced  in  Turkey,  Asia  Minor,  Persia,  India,  China, 
and  other  countries,  but  Smyrna,  Constantinople,  or  Turkey  opium 
is  the  only  variety  recognised  by  the  majority  of  the  pharma- 
copoeias. Persian  and  East  Indian  opiums  are  imported  chiefly  as 
sources  of  the  opium  alkaloids.^  Chinese  opium  is  wholly  con- 
sumed locally. 

1  It  is  possible  that  certain  thebaine  salts  are  soluble  in  chloroform  (as  are 
those  of  codeine),  and  are  dissolved  as  such  by  agitating  their  aqueous  solutions 
with  chloroform. 

2  The  variety  of  poppy  cultivated  in  Asia  Minor  is  said  to  be  the  black, 
which  usually  has  purple  flowers,  and  black,  though  occasionally  white,  seeds. 
It  is  said  to  be  usually  richer  in  morphia  than  that  from  the  white- f\ovfeviug 
and  white-seeded  poppy,  which  is  rich  in  narcotine,  and  appears  to  be  the  only 
kind  cultivated  in  Egypt,  Persia,  India,  China,  and  Japan.  (For  a  chemical 
distinction  between  Turkey  and  Indian  opium,  see  page  330.) 


COMPOSITION  OF  OPIUM.  333 

Opium  varies  considerably  in  appearance,  composition,  and 
quality,  according  to  its  origin  and  mode  of  preparation.^ 

Opium  is  remarkable  for  the  large  number  of  definite,  highly  com- 
plex, crystalline  principles  contained  in  it.  Of  these  the  majority  are 
alkaloids,  a  list  of  which  is  given  on  page  204.  In  addition, 
opium  contains  acetic,  lactic,  and  meconic  acids,  the  last 
substance  being  peculiar  to  opium.  Besides  these  bodies  and  the 
inorganic  constituents,  opium  also  contains  the  indifferent 
bodies  meconin,  meconoiosin,  and  o  p  i  o  n  i  n,  and  a  variety 
of  sugar;  together  with  gummy  and  pectous  matters,  albumin, 
wax,  fat,  caoutchouc,  resin,  and  a  humoid  acid.  Woody  fibre  and 
other  extraneous  matters  are  also  frequently  present ;  but  genuine 
opium  is  wholly  free  from  both  starch  and  tannin. 

The  following  may  be  taken  as  the  general  composition  of  opium : — 


Per  Cent. 

Morphine, 

•1 

6  to  15, 
average  8 

Narcotine, 

4  to  8 

Other  alkaloids, 

0-5  to  2 

Meconin, 

under  1 

Meconic  acid, 

.- 

3  to  8, 
average  4 

Peculiar  resin  and  caout 
chouc, 

- 

5  to  10 

Per  Cent. 

Fat,      .... 

1  to    4 

Gum  and  soluble  humoid  \ 
acid  matters,      .         .  j" 

40  to  56 

Insoluble    matters    and 
mucus, 

18  to  20 

Ash,     .... 

4  to    8 

Water, 

8  to  30, 

average  20 

Alkaloids.  Morphine  is  the  most  abundant  of  the  bases  of 
opium,  and  the  most  valuable  of  the  constituents.  Most  of  the 
pliarmacopoeias  require  dried  opium  to  contain  not  less  than  10  per 
cent,  of  morphine.  Good  Smyrna  opium  deprived  of  water  usually 
contains  from  12  to  15  per  cent,  of  morphine,  though  cakes  from 
the  same  case  are  apt  to  vary  considerably ;  but  if  the  proportion 
be  below  10  per  cent,  on  the  dry  substance,  adulteration  may  be 
suspected.  Egyptian  opium  is  poorer  in  morphine  thpn  that  from 
Asia  Minor,  the  proportion  ranging  from  6  to  12  per  cent.,  but  it 
contains  a  larger  proportion  of  narcotine.  Persian  opium  is 
extremely  variable  in  quality,  probably  partly  in  consequence  of 
the  practice  of  mixing  it  with  sugar  and  other  adulterants,  though 
much  of  it  is  equal  to  ordinary  Turkish  opium.  East  Indian  opium 
is,  as  a  rule,  remarkably  weak  in  morphine,  the  proportion  being 

^  The  product  of  Asia  Minor  is  described  in  the  British  Pharmacopoeia  (1885) 
as  follows  ; — *'  In  rounded,  irregularly  formed,  or  flattened  masses,  varying  in 
weight,  but  commonly  about  eight  ounces  to  two  pounds,  usually  covered  with 
portions  of  poppy  leaves,  and  scattered  over  with  the  reddish-brown  chafiy  fruits 
of  a  species  of  Rumex.  When  fresh,  plastic  and  internally  somewhat  moist, 
coarsely  granular,  and  reddish-  or  chestnut-browu,  but  becoming  harder  by 
keeping,  and  darkening  to  blackish-brown.  Odour  strong,  peculiar,  narcotic, 
taste  nauseously  bitter." 


334  ALKALOIDS  OF  OPIUM. 

sometimes  as  low  as  2|  per  cent.,  more  commonly  between  3J  and 
5,  and  occasionally  as  high  as  8  or  9  per  cent.  This  inferiority  is 
probably  partly  due  to  climate  and  partly  to  defective  methods  of 
■collection  and  preparation.^  The  variety  known  as  "  Patna  garden 
opium"  is  prepared  specially  for  medical  use,  and  contains  from  7  to 
8  per  cent,  of  morphine.  In  Chinese  opium,  the  proportion  of  mor- 
phine is  generally  low.  French  opium  yielded  Guibourt  from 
14*4:  to  22'8  of  morphine,  and  German  from  165  to  20  per  cent. ; 
that  from  the  white  poppy  containing,  according  to  B  i  1 1  z,  6 '8  per 
<jent.  (?)  Algerian  opium  from  red  poppies  yielded  10*4  to  17*8 
per  cent,  of  morphine,  and  from  white  poppies  1*5  to  8*5  per 
-cent.  (?)  In  United  States  opium,  the  proportions  of  morphine 
•observed  have  ranged  from  7 "4  to  10*2  per  cent. 

The  morphine  in  opium  is  usually  stated  to  exist  in  combination 
with  meconic  acid,  but  D  o  1 1  has  shown  that  morphine  ordinarily 
exists  in  opium  partly  as  meconate  and  partly  as  sulphate.^  In 
some  cases  traces  of  acetate  and  lactate  are  present. 

Narcotine  exists  in  opium  in  widely  varying  proportions  and 
often  in  considerable  abundance.  Upwards  of  10  per  cent,  has 
been  occasionally  met  with.  East  Indian  opium  always  contains 
more  narcotine  than  morphine,  whilst  French  opium  sometimes 
affords  neither  narcotine,  narceine,  nor  thebaine. 

The  narcotine  in  opium  is  generally  assumed  to  be  uncombined, 
as  it  is  readily  extracted  by  treating  the  original  (dried)  substance 
with  ether  or  benzene ;  but  as  narcotine  is  readily  removed  from 
the  acidulated  solutions  of  most  of  its  salts  by  agitation  with  a 
suitable  solvent,  such  as  chloroform  or  benzene,  it  does  not  follow 
that  its  extraction  from  opium  is  due  to  its  presence  in  a  free 
state.  It  most  probably  usually  exists  as  meconate.  Occasionally 
the  narcotine  resists  the  action  of  solvents,  unless  the  sample  of 
opium  has  been  previously  treated  with  ammonia.^ 

^Aubergier  states  that  in  one  case  the  product  contained  18  per  cent,  of 
morphine,  while  the  opium  from  a  neighbouring  farm,  where  the  collection 
was  made  somewhat  later,  contained  only  11  per  cent. 

2  Pharm.  Jour.  [3],  xiv.  389.  This  conclusion  is  based  on  the  following 
observations  : — 1.  An  alcoholic  extract  of  opium  contains  sulphuric  acid, 
which  cannot  be  in  combination  with  alkaloids,  as  metallic  sulphates  are 
insoluble  in  alcohol.  2.  An  aqueous  extract  of  opium  contains  sulphuric  acid 
in  quantity  sufficient  to  combine  with  the  whole  of  the  morphine.  3.  The 
same  extract  contains  meconic  acid  in  quantity  insufficient  to  convert  all  the 
morphine  into  meconate.  4.  The  same  extract  contains  inorganic  and  organic 
bases  with  which  the  sulphuric  acid  will  unite  in  preference  to  the  morphine, 
and  the  remainder  of  the  sulphuric  acid  will  not  suflBce  to  combine  with  all 
the  morphine.     (See  also  Proc.  Roy.  Soc.  Edin.,  1882-83,  page  189.) 

3  Twelve  samples  of  opium  analysed  by  Fliickiger  {Pharm.  Jour.  [3], 


ALKALOIDS   OF  OPIUM. 


335 


PorpTiyroxine,  according  toKanny  LallDey  {Pliarm.  Jour.y 
[3],  xii.  397),  i?  a  definite  basic  substance,  always  present  in 
Indian  opium,  but  absent  from  Turkey  or  Smyrna  opium.  Dey 
regards  its  presence  as  so  constant  and  characteristic  of  Indian 
opium  that  he  utilises  it  in  toxicological  investigations.  (See 
page  330.) 

The  other  alkaloids  of  opium  have  been  observed  in  the  follow- 
ing proportions  : — 


Codeine,  0*2  to  0*4  per  cent. 
Codamine,  0'003  per  cent. 
Cryptopine,  very  small. 
Lanthopine,  0*005  per  cent. 
Laudanine,  0-005  percent. 


Narceine,  0*02  to  O'l  (0-7)  per  cent' 
Papaverine,  1  "0  per  cent. 
Pseudomorpliine,  0'02  percent. 
Rhoeadine,  minute. 
Thebaine,  0*15  to  1  '0  per  cent.^ 


Meconin.     Opianyl. 


^10^10^4> 


or  C, 


5H2  \  co.o  I 


Meconin  is  an  indifferent  body,  crystallising  in  colourless,  shin- 
ing, six-sided  prisms,  which  melt  under  water  at  77°  C,  or  alone 
at  110°,  and  distil  at  155°.  It  is  odourless,  bitter,  and  readily 
soluble    in    alcohol    and  chloroform,  but  only  sparingly  in  ether. 

V.  845)  gave  the  following  analytical  results.    The  proportions  of  morphine  are 
most  probably  sensibly  below  the  truth. 


Ethereal  Extract,  consisting  of 

Morphine. 

Description  of  Opium. 

Pure 
Narcotine. 

Wax. 

Crude  Narcotine. 

Crude. 

Pure. 

1.  Patna,  .... 

14-2 

10-0 

4-0 

11-2 

8-6 

2.  Indian  (1852-53), 

12-7 

9-0 

6-1 

11-2 

4-3 

8.  Akbari,         .       .        . 

13-5 

8-5 

5-5 

14-2 

8-5 

4.  Behar,  . 

. 

13-0 

7-6 

4-5 

10-6 

4-6 

5.  Malwa, 

6-5 

7-6 

4-7 

14-4 

61 

6.  Synd,    . 

9-4 

8-0 

3-1 

8-8 

7.  Hyderabad, . 

10-7 

9-7 

5-4 

'". 

3-2 

8.  Candeish,     . 

... 

7-7 

... 

6-1 

9.  Persian, 

14-8 

lb"2 

6-4 

... 

71 

10.  Egyptian,     . 

11-5 

12-2 

8-7 

... 

5-8 

11.  Playford,  Suflfolk  (1823), 

8-8 

9-3 

6-0 

4-3 

12.  English  (1859),     . 

12-0 

11-6 

8-1 

... 

8-3 

Assays  of  thirty-eight  samples  of  opium,  published  by  M.  Adrian, 
showed  a  proportion  of  morphine  exceeding  7  per  cent,  in  all  but  two  cases, 
the  average  being  10  per  cent.  The  narcotine  averaged  2'5  per  cent.,  but 
bore  little  relation  to  the  proportion  of  morphine.  A  sample  showing  only 
3*87  percent,  of  morphine  contained  3*45  of  narcotine,  while  other  samples 
contained  over  10  per  cent,  of  morphine  and  only  the  same  percentage  of 
narcotine.  This  variation  is  doubtless  the  reason  why  some  samples  of  opium 
cause  little  or  no  headache  and  others  occasion  very  disagreeable  symptoms. 

1  Narceine  often  occurs  more  abundantly  than  thebaine. 


336  MECONIN.      OPIONIN. 

Meconin  may  be  readily  crystallised  from  boiling  water,  in  which 
it  is  moderately  soluble. 

The  meconin  contained  in  opium,  in  which  it  exists  in  the  pro^ 
portion  of  less  than  1  per  cent.,  is  probably  a  decomposition-product 
of  narcotine,  from  which  base  it  may  be  prepared  by  heating  with 
nitric  acid. 

Meconin  is  extracted  from  its  acidulated  aqueous  solution  by 
agitation  with  benzene,  chloroform,  or  amylic  alcohol,  the  first- 
named  solvent  being  preferable.  Meconin  dissolves  in  concentrated 
sulphuric  acid,  without  at  first  producing  any  coloration ;  but  the 
solution  gradually  assumes  a  greenish  tint,  changing  to  reddish  in 
the  course  of  twenty-four  hours.  If  the  liquid  be  then  warmed, 
the  colour  changes  to  emerald-green,  blue,  and  purple,  finally 
becoming  red.  The  shades  and  order  of  the  colours  obtained 
depend  much  on  the  proportion  of  acid  used,  the  tints  being  bluer 
and  the  reaction  more  delicate  with  a  small  quantity.  Evaporated 
with  slightly  diluted  sulphuric  acid,  meconin  gives  a  green  colora- 
tion. In  concentrated  hydrochloric  acid  it  dissolves  without 
change  of  colour,  even  on  heating.  If  meconin  be  dissolved  in 
strong  sulphuric  acid  and  a  minute  fragment  of  potassium  nitrate 
added,  a  yellow  coloration  is  obtained,  rapidly  changing  to  a  fine 
scarlet,  which  fades  slowly  and  is  changed  to  yellow  on  heating. 
The  reaction  is  delicate. 

An  aqueous  solution  of  meconin  gives  precipitates  of  characteristic 
microscopic  appearance  with  iodised  potassium  iodide  and  a  solu- 
tion of  bromine  in  hydrobromic  acid  (T.  6.  W  o  r  m  1  e  y). 

Meconoisin,  CgHjoOg,  was  obtained  in  brown,  leaf-like  crystal- 
line masses  from  the  mother-liquors  left  on  the  isolation  of  meconin. 
When  pure  it  is  colourless,  freely  soluble  in  alcohol,  ether,  and  hot 
water,  fuses  at  88°,  and  on  evaporation  with  somewhat  diluted 
sulphuric  acid  yields  a  red  colour,  changing  to  purple. 

Opionin,  according  to  Hesse,  is  contained  in  small  quantities 
in  Smyrna  opium.  It  forms  white  needles  which  melt  at  227° 
and  contain  no  nitrogen.  It  is  insoluble  in  water,  but  dissolves  in 
alkalies,  alcohol,  and  ether.  When  boiled  with  milk  of  lime, 
opionin  is  decomposed,  an  acid  being  formed  which  is  freely  soluble 
in  water  and  ether,  and  gives  a  bulky  precipitate  with  lead  acetate 
in  alkaline  solutions. 

Meconio  Acid,  C7H^07  =  C5H02(0H):(C0.0H)2.  This  sub- 
stance is  characteristic  of  opium,  in  which  it  exists  chiefly  in  com- 
bination with  the  alkaloids,  but  sometimes  a  portion  of  it  appears 
to  be  present  in  a  free  state. 

Meconic  acid  may  be  prepared  from  opium  by  precipitating  the 
neutralised  aqueous  solution  of    the  drug  with  calcium  chloride, 


MECONIC  ACID.  337 

filtering,  and  decomposing  the  precipitate  of  calcium  meconate  by 
repeated  treatment  with  warm  diluted  hydrochloric  acid.  A  pre- 
ferable plan  is  to  precipitate  the  aqueous  solution  of  opium  with 
neutral  lead  acetate,  filter,  suspend  the  precipitate  in  water,  and 
decompose  it  with  a  stream  of  sulphuretted  hydrogen.  The  filtered 
and  concentrated  solution  deposits  meconic  acid  on  addition  of 
hydrochloric  acid.  The  product  may  be  purified  by  re-solution  in 
hot  water,  cooling,  and  adding  hydrochloric  acid.  Meconic  acid 
may  also  be  conveniently  prepared  by  precipitating  it  as  the 
calcium  salt,  decomposing  this  with  a  slight  excess  of  oxalic  acid, 
filtering,  and  concentrating. 

Meconic  acid  crystallises  in  micaceous  scales  or  small  rhombic 
prisms  containing  3  aqua.  On  being  heated  to  100°,  it  loses  its 
water  of  crystallisation  and  leaves  a  white  effloresced  mass.  At 
120°  C.  it  splits  up  into  carbon  dioxide  and  comenic  acid, 
CgH^Og,  which  at  a  higher  temperature  again  loses  carbon  dioxide, 
and  forms  pyromeconic  acid,  CgH^Og.^  Comenic  acid  is  but 
sparingly  soluble  in  hot,  and  is  almost  insoluble  in  cold  water. 
In  absolute  alcohol  it  is  quite  insoluble.  Meconic  acid  dissolves 
in  1 1 5  parts  of  cold,  or  4  parts  of  boiling  water ;  its  solubility 
in  the  cold  is  diminished  by  addition  of  hydrochloric  acid,  which 
therefore  causes  a  precipitate  in  strong  solutions.  When  the  solu- 
tion of  meconic  acid  is  boiled  for  some  time,  especially  if  hydro- 
chloric acid  be  present,  comenic  acid  is  formed,  and  crystallises 
out  as  the  liquid  cools.  The  aqueous  solution  of  meconic  acid  has 
a  sour  astringent  taste,  and  strongly  acid  reaction. 

Meconic  acid  is  freely  soluble  in  alcohol  (distinction  from 
comenic  acid)  and  is  deposited  in  fine  crystals  on  spontaneous 
evaporation  of  the  solution.  It  is  much  less  readily  soluble  in 
ether  and  is  almost  wholly  insoluble  in  chloroform. 

Nitric  acid  readily  acts  on  meconic  acid,  much  oxalic  acid 
being  formed. 

Meconic  acid  derives  its  chief  analytical  interest  from  the  fact 
that  it  is  strictly  'peculiar  to  opium  and  its  preparations,  and  hence 


^  The  relationship  between  these  three  bodies  appears  to  be  as  follows  : — 
(OH  (OH  roH 

C5HO2  \  Ct  ).0H  CgHOa  \  H  aHOg  \  H 

(CO.OH  (CO.OH  (H 

Meconic  acid.  Comenic  acid.  Pyromeconic  acid. 

Comenic  acid  forms  prisms,  laminae  or  granules,  insoluble  in  alcohol, 
soluble  in  16  parts  of  boiling  water,  but  deposited  on  cooling. 

Pyromeconic  or  pyrocomenic  acid  contains  no  carboxyl-group,  and  its 
acid  characters  are  very  feebly  marked.  It  cr3'^stallises  in  prisms,  is  readily 
soluble  in  water  and  alcohol,  melts  at  117°,  and  boils  at  227°,  but  sublimes 
slowly  at  the  ordinary  temperature  and  readily  at  100°. 

VOL.   III.   PART  II.  y 


338  REACTIONS    OF  MECONIC  ACIb. 

its  positive  detection  is  a  decided  proof  of  tlie  presence  of  a 
preparation  of  opium.     It  is  not  poisonous. 

The  microscopic  appearance  of  the  precipitates  produced  in 
not  too  dilute  solutions  of  meconic  acid  or  soluble  meconates  by 
barium  chloride,  calcium  chloride,  potassium  ferrocyanide,  and 
hydrochloric  acid  are  highly  characteristic. 

The  most  characteristic  reaction  of  meconic  acid  is  the  forma- 
tion of  a  deep  purplish  red  coloration  on  adding  ferric  chloride  to 
the  solution  of  meconic  acid  or  a  meconate.  The  shade  of  colour 
is  distinctly  different  from  that  of  the  ferric  acetate  or  formate, 
and  the  ferric  meconate  also  differs  from  these  in  not  being  readily 
destroyed  by  boiling,  or  by  adding  cold  dilute  hydrochloric  acid, 
and  from  the  ferric  tliiocyanate  in  being  unaffected  on  addition  of 
mercuric  chloride  or  auric  chloride.^  If  any  doubt  exist  as  to  the 
presence  of  an  acetate,  it  is  desirable  to  precipitate  the  neutralised 
solution  with  nitrate  or  neutral  acetate  of  lead,  wash  the  precipi- 
tated lead  meconate  thoroughly,  suspend  it  in  water,  and  decompose 
it  with  sulphuretted  hydrogen.  After  evaporating  the  filtered 
liquid  at  a  gentle  heat  to  drive  off  the  excess  of  sulphuretted 
hydrogen,  the  test  with  ferric  chloride  may  be  safely  applied. 
Instead  of  adding  ferric  chloride  to  the  solution  of  meconic  acid, 
the  reagent  may  be  applied  to  the  solid  substance,  as  obtained  by 
the  evaporation  of  its  aqueous  or  ethereal  solution. 

The  red  coloration  produced  by  meconic  acid  and  a  ferric  salt 
is  much  weakened  by  oxalic  and  phosphoric  acids,  and  still  more 
so  by  metaphosphoric  acid, 

Comenic  and  pyromeconic  acids  also  strike  a  red  coloration  with 
ferric  chloride,  but  with  the  latter  acid  the  colour  is  less  deep. 

Meconic  acid  may  be  extracted  from  its  acidulated  solutions 
by  agitation  with  ether,  a  property  which  enables  it  to  be  readily 
separated  from  morphine,  acetic  acid,  tannin,  and  other  substances 
liable  to  interfere  with  the  observance  of  its  reaction  with  ferric 
chloride.  The  extraction  is  not  perfect,  even  when  several  times 
repeated,  and  hence  the  method  cannot  be  employed  for  quantita- 
tive purposes. 

Meconic  acid  may  be  determined  by  converting  it  into  a  lead  salt, 
or  colorimetrically  by  ferric  chloride,  by  comparing  the  depth  of  tint 
produced  by  the  sample  with  that  obtained  by  treatment  with  a 
known  quantity  of  opium.  "Very  fair  approximate  estimations  of 
meconic  acid,  and  less  accurately  of  opium,  may  be  made  in  this  way, 
even  when  the  quantity  of  material  at  disposal  is  very  insignificant. 

Three  of  the  atoms  of  hydrogen  in  meconic  acid  are  replaceable 

^  Thiocyanates  (sulphocyanides)  exist  in  sensible  quantity  in  the  saliva 
(and  hence  in  the  contents  of  the  stomach)  and  also  in  white  mustard. 


METALLIC  MECONATES.  339 

by  metals,  but  recent  researches  have  shown  that  the  acid  is,  pro- 
perly speaking,  dibasic,  only  two  carboxyl  groups,  CO.OH.,  being 
present.  The  third  atom  of  hydrogen  belongs  to  hydroxyl,  and  when 
this  is  replaced  by  metals  basic  salts  of  a  yellow  colour  result. 

The  metallic  meconates  are  mostly  insoluble  in  water,  except  the 
meconates  of  the  alkali-metals.  They  are  nearly  all  insoluble  in 
alcohol,  and  are  but  slightly  affected  by  acetic  acid.  The  salts 
having  two  atoms  of  basic  hydrogen  replaced  by  metals  are  neutral 
to  litmus  paper. 

Acid  Calcium  Meconate,  CaH2[C7H(OH)Og]2,  is  precipitated  as 
a  sparingly  soluble  salt  of  characteristic  microscopic  appearance 
on  adding  calcium  chloride  to  not  too  dilute  a  solution  of 
meconic  acid  or  a  soluble  meconate.  In  presence  of  free  ammonia, 
less  soluble,  yellow,  dicalcic  meco7iate,  Ca2[CijrH(OH)Og]2,  is  precipi- 
tated. On  treating  either  of  these  salts  with  hot  dilute  hydrochloric 
acid,  meconic  acid  crystallises  out  on  cooling. 

Iron  Meconates.  Ferrous  meconate  is  a  colourless,  very 
soluble  salt,  which  turns  red  on  exposure  to  air.  Ferric  meconate 
exists  in  the  purple-red  liquid  produced  on  adding  a  ferric  salt  to 
a  soluble  meconate. 

Lead  Meconate  is  obtained  by  precipitating  meconic  acid  or  a 
meconate  (or  an  aqueous  solution  of  opium)  with  neutral  acetate 
of  lead.  The  triplumbic  meconate  is  stated  to  be  formed  even  in 
presence  of  excess  of  meconic  acid,  but  it  is  more  probably 
a  mixture  or  compound  of  the  normal  meconate,  VhQ>^<f)rj,  with 
lead  hydroxide.  The  precipitate  is  quite  insoluble  in  cold  and 
boiling  water,  and  is  not  affected  by  acetic  acid. 

Morphine  Meconate  has  already  been  described  (page  313). 

Action  of  Solvents  on  Opium. 

The  action  of  different  solvents  and  reagents  on  opium  and  its 
constituents  is  shortly  as  follows  :  — 

Water  dissolves  meconic  acid  readily,  as  also  sulphate,  meconate, 
and  acetate  of  morphine.  The  morphine  is  very  sparingly  soluble 
in  cold  water,  and  narcotine  still  less  so.  Narceine  is  much  more 
soluble  than  morphine,  while  the  resin,  caoutchouc,  &c.,  are 
insoluble,  though  certain  gummy  matters  pass  into  solution. 

Alcohol  dissolves  free  morphine  as  well  as  the  acetate  and 
meconate.  The  other  alkaloids  of  opium,  as  also  the  resin  and 
caoutchouc,  are  dissolved  by  alcohol. 

Amylic  alcohol  dissolves  all  the  alkaloids  of  opium,  if  in  a  free 
state.     The  resin  also  is  slightly  soluble  in  auiylic  alcohol. 

Ether  J  benzene^  and  carbon  disulphide  dissolve  only  about  '05  per 
cent,  of  free  morphine,  but  the  other  free  alkaloids  of  opium  more 
readily.  These  solvents  also  dissolve  the  caoutchouc, but  not  the  resin. 


340  ACTION  OF  SOLVENTS  ON  OPIUM. 

Acids  dissolve  all  the  alkaloids  from  opium,  together  with  a 
resinoid  substance. 

Fixed  alkalies,  used  in  excess,  dissolve  morphine  freely,  while 
narcotine  remains  insoluble.  Lime  water  dissolves  morphine,  but 
is  a  solvent  for  narcotine  only  in  presence  of  morphine.  The  resin 
ot  opium  is  partly  soluble  in  alkalies. 

Ammonia  dissolves  morphine  sparingly,  narceine  and  codeine 
readily,  while  the  other  alkaloids  and  the  resin  of  opium  are 
insoluble. 

From  the  foregoing  statements,  the  arrangement  of  which  is 
mostly  due  to  E.  L.  Cleaver  (Year-Book  Pharm.,  1876,  page  502), 
it  follows  that  an  aqueoits  solution  of  opium  will  contain  sulphate 
and  meconate  of  morphine  and  other  alkaloids,  calcium  salts, 
meconic  acid,  extractives,  and  resinous  matter. 

An  alcoholic  solution  will  contain,  in  addition  to  the  above,  free 
narcotine,  caoutchouc,  fat,  and  resin. 

Opium  which  has  been  exhausted  with  water  still  retains  a 
bitter  taste,  but  this  is  probably  due  to  narcotine,  as  it  is  removed 
by  carbon  disulphide,  benzene,  or  ether,  in  which  morphia  and  its 
salts  are  insoluble.  Water,  even  when  cold,  may  be  trusted  to 
dissolve  the  whole  of  the  morphine  from  opium,  if  the  resultant 
solution  be  distinctly  acid.  In  some  processes  of  assaying  opium, 
the  sample  is  subjected  to  a  preliminary  treatment  with  benzene, 
chloroform  or  ether  to  remove  narcotine,  caoutchouc,  and  colouring 
matter  (see  page  349).  By  this  means  the  subsequent  exhaustion 
with  water  is  much  facilitated,  and  a  purer  solution  of  morphine  is 
obtained.  Li  presence  of  much  narcotine,  morphine  is  soluble  in 
benzene,  but  this  is  not  true  of  the  sulphate,  meconate,  or  other  salts 
of  morphine.  Hence  there  is  no  loss  of  morphine  on  extracting 
opium  with  benzene.  Meconate  of  morphine  is,  however,  freely 
soluble  in  a  mixture  of  alcohol  and  chloroform ;  but  the  simultaneous 
presence  of  ether  prevents  its  solution  more  or  less  completely. 

Adulterations  and  Assay  of  Opium. 

Opium  is  liable  to  a  variety  of  adulterations,  some  of  which  are 
of  a  very  gross  kind.  Sand,  clay,  ashes,  stones,  shot,  buUets,  lead 
turnings  and  other  make-weights  are  occasionally  met  with.  Sugar, 
gum  tragacanth,  pulp  of  apricots  and  figs,  pounded  poppy-capsules, 
and  other  vegetable  substances  of  a  saccharine,  mucilaginous,  and 
resinous  nature  are  also  employed.  Aqueous  extracts  of  poppies 
and  of  Glaudum  luteum  are  said  to  be  sometimes  added  in  Turkey, 
though  rarely  if  ever  seen  in  the  opium  imported  into  England. 
Such  adulterants  are  indicated  by  the  darker  colour  and  hygroscopic 
character  of  the  product,  by  the  difficulty  in  filtering  the  solution, 
and  by  the  continuous  streak  which  the  sample  leaves  when  drawn 


ADULTERATIONS   OF  OPIUM. 


341 


across  a  sheet  of  paper,  whereas  good  opium  makes  an  interrupted 
mark. 

The  proportion  of  ash  yielded  by  opium  should  not  exceed  8  per 
cent.  The  proportion  of  water  in  opium  averages  about  20  per  cent., 
the  usual  range  being  from  1 5  to  28  per  cent.  It  is  best  determined 
by  taking  a  known  weight  of  the  opium  in  thin  slices,  and  noting 
the  weight  on  drying  at  100°  C. 

The  extract  of  opium  is  determined  by  exhausting  the  dried 
sample  with  cold  water,  and  collecting,  drying,  and  weighing  the 
residue ;  or  evaporating  the  whole  or  an  aliquot  part  of  the  solu- 
tion to  dryness,  and  weighing  the  extractive  matter  left.  Should 
the  insoluble  residue  exceed  40  to  45  per  cent,  of  the  dried  sample 
(equal  to  a  minimum  of  55  per  cent,  of  extract),  the  presence  of 
sand,  clay,  or  other  insoluble  (mineral)  adulterants  is  probable ; 
while  if  the  residue  is  below  this  proportion  the  presence  of  sugar, 
gum,  or  other  soluble  impurity  is  indicated.^ 

^  According  to  H a n  b u r  y  and  Fliickiger,  dried  opium  from  Asia  Minor 
should  yield  from  55  to  66  per  cent. — generally  more  than  60— of  extractive 
matter  soluble  in  cold  water,  the  proportion  of  extract  from  Indian  opium 
being  from  60  to  68  per  cent. 

The  following  are  determinations  by  D.  B.  Dott  {Year- Book  Pharm.,  1876, 
page  498)  of  the  leading  constituents  of  eighteen  samples  of  opium,  purchased 
from  druggists  of  good  standing  in  London,  Dublin,  and  Edinburgh.  The 
aqueous  extract  was  determined  by  subtracting  the  sum  of  the  water  and 
insoluble  matter  from  100  "00.  The  proportion  of  morphia  calculated  on 
the  dried  opium  averaged  11*06  per  cent.  The  proportion  of  morphia  in  the 
dry  extract  was  18*3  per  cent,  (compare  page  350.) 


Percentage  Composition. 

Description  of  Opium. 

Percentage  of 
Morphine 

Water. 

Insol.  Residue. 

Aqueous 
Extract. 

(liydrated). 

1.  Turkey, 

19-6 

32-60 

47-80 

10-75 

2. 

. 

20-0 

28-85 

51-15 

12-30 

3. 

26-0 

25-95 

48-05 

10  20 

4.         „ 

, 

21-2 

23-70 

55-10 

7-57 

5. 

22-0 

30-95 

47-05 

9-60 

6. 

18-4 

25-45 

56-15 

11-69 

7. 

19-2 

25-90 

54-90 

12  30 

8. 

20-4 

34-20 

45-40 

12-30 

9. 

27-2 

35-80 

37-00 

6-76 

10.         „ 

21-2 

38-80 

40-00 

9-80 

11. 

22-8 

29-70 

47-50 

8-85 

12.         „ 

31-2 

47-90 

20-90 

6-93 

13.  Persian,     . 

14  0 

26-80 

59-20 

6  00 

14. 

12-0 

27-40 

60-60 

8-50 

15.         „ 

16-0 

25-90 

58-10 

2-10 

16.  Malwa,       . 

15-2 

24-10 

60-70 

7-30 

17. 

13-6 

25-20 

61-20 

5-88 

18.  Egyptian,  . 

14-8 

28-30 

56-90 

7-00 

Average 

19-70 

29-86 

50-44 

8-88 

342  ADULTERATIONS   OF  OPIUM. 

Hager  recommends  the  following  additional  tests  for  the 
purity  of  opium : — 25  grains  weight  of  the  previously  dried 
sample  is  triturated  with  half  an  ounce  of  boiling  water,  when  the 
formation  of  a  stiff  paste  will  indicate  the  presence  of  starch,  flour, 
gum,  &c.  2  ounces  of  water  should  next  be  added  and  the  liquid 
filtered.  If  the  filtrate  be  brown  or  of  a  deeper  colour  than 
"wine-yellow,"  the  presence  of  liquorice  or  other  vegetable 
extracts  is  probable.  The  liquid  should  have  an  acid  reaction,  or 
admixture  with  chalk,  litharge,  or  ashes  may  be  suspected.  The 
liquid  should  give  no  reaction  with  potassium  ferrocyanide  (heavy 
metals),  and  if  evaporated  to  one  ounce  and  treated  with  twice  its 
measure  of  alcohol  no  precipitate  should  be  produced  (indicative  of 
adulteration  with  gum  or  certain  salts). 

On  agitating  powdered  opium  with  chloroform,  any  starch  or 
mineral  adulterants  will  settle  out,  and  may  be  weighed  and 
further  examined  microscopically  and  chemically. 

When  moist,  opium  is  very  liable  to  become  mouldy,  and  hence 
should  be  dried  at  a  moderate  temperature  and  carefully  preserved 
from  the  air.  If  kept  in  a  damp  condition,  fungoid  growths  soon 
make  their  appearance,  and  gradually  diminish  and  destroy  the 
aroma  of  the  opium,  besides  materially  reducing  its  alkaloidal  value. 

Determination  of  Morphine  in  Opium.     Morphiometry. 

By  far  the  most  important  item  in  the  examination  of  opium  is 
the  determination  of  the  morphine  present.  The  proportion  of 
this  constituent  varies  considerably,  as  already  stated ;  but  dried 
and  powdered  opium  intended  for  medicinal  use  should  not  assay 
less  than  10  per  cent.^  This  is  the  limit  of  the  German  and 
Austrian  Pharmacopoeias,  while  that  of  the  United  States  allows 
the  range  of  1 2  to  16  per  cent.,  any  richer  opium  to  be  reduced 
within  these  limits  by  mixing  it  with  an  article  of  lower  grade  in 
proper  proportion.  According  to  the  German  and  United  States 
Pharmacopoeias,  opium  in  its  normal  moist  condition  should  yield 
not  less  than  9  per  cent,  of  morphine.  The  British  Pharmacopoeia 
of  1867  allowed  a  range  of  6  to  8  per  cent.;  but  in  the  edition  of 
1885  the  assay  is  directed  to  be  made  on  the  dried  substance, 
the  yield  of  morphine  to  be  between  9^  and  10^  per  cent.^ 

*  The  difficulty  caused  by  the  natural  variations  in  the  quality  of  opium  is 
well  met  by  a  process  patented  by  B.  S.  Proctor,  who  removes  the  greater 
part  of  the  fatty  and  resinous  matters  and  the  worthless  narcotine,  and  reduces 
the  opium  to  a  uniform  rectified  condition,  in  which  it  contains  10  per  cent,  of 
morphine. 

2  "This  standard  is  ridiculously  low,  and  will  have  the  effect  of  depriving 
medicine  of  all  the  best  opium  that  reaches  this  country.  This  standard  is 
about  equal  to  that  of  the  last  Pharmacopceia  ;  but  then  there  was  no  mcKci- 


MORPHIOMETRY.  343 

The  assay  of  opium  for  morphine  has  received  much  attention, 
the  investigators  being  very  numerous  and  the  bibliography  very 
extensive.  The  accurate  determination  of  morphine  in  opium  is 
attended  with  peculiar  difficulties,  and  many  of  the  processes  which 
have  been  published  give  little  better  than  rough  approximations 
to  the  truth,  especially  when  employed  for  the  assay  of  abnormal 
samples.^  Of  the  many  methods  proposed,  the  following  are  among 
the  best : — 

British  PharmacopcBia  Process^ — This  method  of  assay  is  based 
on  : — the  conversion  of  the  resinous  matters  of  opium  into  insoluble 
lime  compounds;  the  decomposition  of  the  morphine  meconate 
with  formation  of  insoluble  calcium  meconate  ]  the  solubility  of 
the  resultant  free  morphine  in  lime-water ;  the  decomposition  of 
the  solution  by  ammonium  chloride,  with  formation  of  calcium 
chloride,  ammonia,  and  free  morphine ;  the  use  of  alcohol  to  dis- 
solve impurities,  and  of  ether  to  promote  the  crystallisation  of  the 
alkaloid ;  and  the  collection,  washing,  and  weighing  of  the  morphine 
thus  obtained.  The  following  are  the  details  of  the  process  as  laid 
down  in  the  British  Pharmacopoeia  of  1885  : — 

"Take  of  powdered  opium,  dried  at  212°  F.  (  =  100°  C),  140 
grains ;  lime,  freshly  slaked,  60  grains ;  chloride  of  ammonium, 
40  grains ;  rectified  spirit,  ether,  distilled  water,  of  each  a  suffici- 
ency. Triturate  together  the  opium,  lime,  and  400  grain-measures 
of  distilled  water  in  a  mortar  until  a  uniform  mixture  results;  then 
add  1000  grain-measures  of  distilled  water,  and  stir  occasionally 
during  half  an  hour.  Filter  the  mixture  through  a  plaited  filter 
about  3  inches  in  diameter  into  a  wide-mouthed  bottle  or  stoppered 

mum  standard  given.  It  is  all  very  well  to  standardise  preparations,  but,  I 
think,  it  is  going  too  far  when  we  attempt  it  with  natural  products  ;  but  if  we 
are  to  have  a  maximum  and  minimum  standard  for  opium,  let  it  be  one  which 
will  include  the  best  and  exclude  the  inferior  and  adulterated  kinds,  instead 
of  the  reverse,  as  now  obtains.  To  attain  this  it  would  he  necessary  to  raise 
the  standard  at  least  2  per  cent." — (M ichael  Conroy,  Pharm.  Jour,^  [3], 
xvi.  378.) 

^  The  sampling  of  opium  for  the  purpose  of  analysis  is  not  always  an  easy 
operation,  and  is  not  conducted  on  a  uniform  plan.  J.  B.  Nagelwoort 
recommends  that  a  small  slice  should  be  cut  by  a  knife  from  the  interior  oi 
each  lump  of  the  lot,  these  pieces  mixed  together,  and  10  grammes  taken  for 
the  determination  of  moisture.  The  remainder  is  dried,  pulverised,  and  the 
residual  moisture  and  morphine  determined  in  it. 

2  This  method  was  originally  devised  by  P  o  r  t  e  s  and  Langlois  {Chem. 
News  xlv.  67),  and  with  slight  alterations  was  adopted  by  the  Societe  de 
Pharraacie  of  Paris,  and  made  official  in  the  United  States  Pharmacopoeia  of 
1880.  It  was  further  improved  by  M.  Conroy  {Pharm.  Jour.y  [3],  xv.  473), 
and  adopted  as  the  official  test  in  the  British  Pharmacopoeia  of  1885. 


344  ASSAY  OF  OPIUM. 

flask  (having  the  capacity  of  about  six  fluid  ounces,  and  marked  at 
exactly  1040  grain-measures)  until  the  filtrate  reaches  this  mark.-^ 
To  the  filtered  liquid  (representing  100  grains  of  opium)  add  110 
grain-measures  of  rectified  spirit,  and  500  grain-measures  of  ether, 
and  shake  the  mixture  ;  then  add  the  chloride  of  ammonium,  shake 
well  and  frequently  during  half  an  hour,  and  set  it  aside  for  twelve 
hours.^  Counterbalance  two  small  filters ;  place  one  within  the 
other  in  a  small  funnel,  and  decant  the  ethereal  layer  as  completely 
as  practicable  upon  the  inner  filter.  Add  200  grain-measures  of 
ether  to  the  contents  of  the  bottle  and  rotate  it ;  again  decant  the 
ethereal  layer  upon  the  filter,  and  afterwards  wash  the  latter  with 
100  grain-measures  of  ether  added  slowly  and  in  portions.  IsTow, 
let  the  filter  dry  in  the  air,  and  pour  upon  it  the  liquid  in  the 
bottle  in  portions,  in  such  a  way  as  to  transfer  the  greater  portion 
of  the  crystals  to  the  filter.  When  the  fluid  has  passed  through 
the  filter,  wash  the  bottle  and  transfer  the  remaining  crystals  to  the 
filter,  with  several  small  portions  of  distilled  water,  using  not  much 
more  than  200  grain-measures  in  all,  and  distributing  the  portions 
evenly  upon  the  filter.  Allow  the  filter  to  drain,  and  dry  it,  first 
by  pressing  between  sheets  of  bibulous  paper,  and  afterwards  at  a 
temperature  between  131°  and  140°  F.  (55°  and  60°  C),  and 
finally  at  194°  to  212°  F.  (90°  to  100°  C).  Weigh  the  crystals 
in  the  inner  filter,  counterbalancing  by  the  outer  filter.  The 
crystals  should  weigh  10  grains,  or  not  less  than  9  J,  and  not  more 
than  10  J  grains,  corresponding  to  about  10  per  cent,  of  morphine 
in  the  dry,  powdered  opium." 

The  skilled  chemist  will  find  abundant  opportunity  for  im- 
proving on  the  method  of  manipulation  prescribed  in  the  above 
process.  He  will  probably  substitute  their  equivalents  in  grammes 
and  centimetres  for  the  weighed  and  measured  grains  prescribed ; 
but  he  will,  in  practice,  find  it  advantageous  to  increase  the 
weights  of  opium  and  lime  taken  to  10  grammes  and  5  grammes 
respectively,  and  the  measure  of  the  water  to  100  c.c.  52  c.c. 
of  the  filtrate  wiU  then  represent  5  grammes  of  the  opium,  and 
the  delay,  consequent  on  collecting  so  large  a  portion  as  f  of  the 

1  The  additional  40  grain-measures  is  intended  as  an  allowance  for  the  aver- 
age increase  in  the  volume  of  the  liquid  caused  by  the  extractive  matter  of  the 
opium. 

*  "The  use  of  an  excess  of  ether,  much  beyond  ether-saturation,  so  as  to 
cause  an  ethereal  layer  to  rise  above  the  crystallising  liquid,  along  with  the 
frequent  shaking  up  of  the  ether  with  the  aqueous  liquid  in  the  closed  flask 
during  crystallisations,  marks  an  important  advance  in  opium  assay."— (A.  B. 
Prescott.)  The  practice  has  been  adopted  in  all  recent  methods  of  assaying 
opium. 


MORPHIOMETRY.  345 

liquid,  will  be  avoided.*  A  less  clumsy  means  will  be  adopted  for 
measuring  the  exact  quantity  of  the  filtrate  required  than  that  of 
relying  on  a  mark  made  on  the  side  of  a  6  oz.  bottle,  or  the  broad 
part  of  a  flask ;  and  the  ethereal  layer  will  be  removed  by  some 
form  of  pipette  instead  of  attempting  to  decant  it  on  the  filter. 

The  B.P.  process  for  the  assay  of  opium  is  tolerably  simple 
and  rapid,  and  when  carefully  executed,  gives  fairly  constant 
results.  As  suggested  by  Conroy,  and  proved  by  Braithwaite 
and  Farr,  the  time  allowed  for  precipitation  of  the  morphine  may 
be  reduced  from  twelve  hours  to  two  without  afi'ecting  the  accuracy 
of  the  results,  but  it  is  safer  to  allow  six  or  eight  hours  to  elapse 
before  filtering.  It  would  be  a  further  improvement  to  direct  that 
the  alkaloid  should  be  titrated  instead  of  being  weighed.  ^  This 
would  be  a  guarantee  of  the  true  nature  and  purity  of  the  pre- 
cipitate, and  would  save  the  time  required  for,  and  uncertainty 
attaching  to,  the  drying  of  the  alkaloid. 

The  results  yielded  by  the  B.P.  process  of  assaying  opium  are 
seriously  ))elow  the  truth,  a  fact  ignored  by  the  editors,  although 
pointed  out  by  M.  Conroy,  whose  process  it  practically  is.^ 

Braithwaite  and  Farr  {Pharm.  Jour.^  [3],  xvii.  398) 
confirm  Conroy's  view,  and  state  that  the  morphine  left  in  solution 
is  about  1  per  cent,  of  the  opium.  But  they  point  out  that  the 
precipitate  contains  an  average  of  7  per  cent,  of  colouring  matter 

*M.  Conroy  states  that,  by  reducing  the  quantities  of  opium  and  water 
recommended  by  him,  the  editors  of  the  Pharmacopoeia  have  deprived  the 
process  of  one  of  its  chief  merits,  with  the  consequence  that  the  1040  grain- 
measures  of  filtrate  required  can  only  be  obtained  at  the  sacrifice  of  much 
time.  A.  C.  Abraham  {Pharm.  Jour.,  [3],  xvi.  380)  endorses  this  view, 
holding  that  "for  the  sake  of  saving  a  few  grains  of  opium,  a  simple  and  quick 
process  had  been  rendered  most  tedious.  The  standard  of  10  per  cent,  was, 
moreover,  so  low  that  he  had  not  yet  succeeded  in  getting  any  genuine  Turkey 
opium  bad  enough  to  stand  it."  (For  the  reply  of  the  editor  (J.  A tt field) 
to  these  and  other  damaging  criticisms,  see  Pharm.  Jour.,  [3],  xvi.  470.) 

2  Titration  of  the  precipitated  morphine  was  directed  by  P  o  r  t  e  s  and 
Langlois,  the  original  proposers  of  the  method  (Jour.  Pharm.  et  Chemie, 
November  1881). 

^  According  to  the  Phannacopceia,  from  9^  to  10|  grains  of  crystals  should 
be  actually  obtained,  "corresponding  to  about  ten  per  cent,  of  morphine  in 
the  dried  powdered  opium,"  a  statement  which  is  materially  inaccurate. 
Conroy  found,  in  test-experiments  on  10  grains  of  pure  morphine,  9*05, 
9*02,  and  9 '06  grains  were  recovered,  thus  showing  a  notable  but  almost 
constant  loss.  The  loss  when  an  aqueous  extract  of  opium  is  operated  on, 
instead  of  a  pure  solution  of  morphine,  is  still  greater,  jtrobably  ranging  from 
1  to  1^  per  cent.  Hence  a  yield  of  9^  to  10^  per  cent,  of  morphine,  by 
the  B.P.  process,  not  improbably  corresponds  to  about  11;^  per  cent,  of 
morphine  actually  present. 


346 


ASSAY  OF  OPIUM. 


as  impurity,  and  hence,  in  assaying  an  opium  containing  14  to  15 
per  cent,  of  morphine,  the  error  from  this  cause  approximately 
balances  that  due  to  imperfect  precipitation.^  On  dissolving  the 
impure  morphine  in  lime-water,  a  large  proportion  of  the  colouring 
matter  is  left  in  the  filter,  and  on  extracting  the  solution  with  ammo- 
nium chloride,  alcohol  and  ether,  as  in  the  B.P.  process,  the  rest  of 
the  colouring  matter  remains  in  solution,  and  the  reprecipitated 
morphine  is  obtained  almost  white.  But  there  is  a  serious  loss 
(10  per  cent,  of  the  weight)  through  solubility  of  the  precipitate. 

J.  Denham  Smith  {Cheni.  Neics,  Ivii.  93,  103)  obtained 
by  the  B.P.  process,  in  five  experiments,  results  ranging  from 
9 "4  to  9'6  per  cent.,  a  sixth  experiment  giving  10*5  per  cent., 
the  true  amount  of  morphine  present  being  stated  at  11*2  per 
cent.,  which  was  obtained  by  a  process  giving  exceptionally  high 
results  (page  347).  Smith  distrusts  the  use  of  lime  as  open  to  many  • 
objections,  and  this  opinion  is  shared  byR.  Williams^  (Chem. 
Neivs,  Ivii.  134),  who  gives  the  following  results  obtained  from 
four  samples  of  opium  when  assayed  by  the  processes  of  the 
British,  American,  and  German  Pharmacopoeias  respectively. 


No.  1. 

No.  2.. 

No.  3. 

No.  4. 

British, 

American,     .... 
Crerman,        .       .       -       . 

10-8 
11-1 
10-2 

10-5 
10-8 
10-0 

7-4 
8-1 
7-1 

12-2 
11-9 
10-6 

In  each  case  the  German  process  gave  the  lowest  result,^  and 
the  American  the  highest,  except  in  the  case  of  No.  4  sample. 

^  Dott  considers  7  per  cent,  of  impurity  excessive,  and  thinks  3  to  5  per 
cent,  would  be  nearer  the  truth. 

'  Notwithstanding  this,  D.  B.  Dott  {Pharm.  Jour. ,  [3],  xix.  83)  considers 
that  the  employment  of  lime  ''has  much  to  be  said  in  its  favour.  It  gives 
a  purer  solution  of  morphine  than  can  be  obtained  by  any  other  single  opera- 
tion, and  besides  eliminates  nearly  all  possible  adulterants.  The  morphine 
precipitated  by  the  ammonium  chloride  is  usually  remarkably  pure,  we  might 
say  always  if  the  opium  is  genuine.  Samples  are,  however,  occasionally  met 
with  which  yield  with  the  chloride  of  ammonium  a  certain  amount  of 
flocculent  precipitate  along  with  the  morphine.  In  such  cases  it  is  pre- 
eminently necessary  to  apply  the  titration  with  standard  acid.  There  can 
be  no  doubt  that  the  editors  of  the  Pharmacopoeia  ought  to  have  allowed  for 
the  inevitable  loss  of  morphine  in  the  mother-waters,  especially  when  any 
other  trustworthy  method  is  permitted." 

'  Various  observers  agree  that  the  results  obtained  by  the  German  method 
of  assay  are  at  least  2  per  cent,  below  the  truth,  and  the  morphine  not  always 
pure  {Pharm.  Jour.,  [3],  xiv.  645). 


MORPHIOMETRY.  347 

The  yield  of  morphine  obtained  by  the  B.P.  process  ought  to 
be  corrected  by  a  definite  allowance,  but  a  more  satisfactory  plan 
would  be  to  prescribe  a  method  by  which  the  remaining  alkaloid 
could  be  recovered  if  desired.  This  might  probably  be  ap- 
proximately effected  by  agitating  the  warm  ammoniacal  filtrate 
with  amylic  alcohol,  and  separating  and  evaporating  the  solvent. 

United  States  Pharmacopoeia  Process. — As  already  stated,  the 
method  of  opium  assay  prescribed  by  the  British  Pharmacopoeia 
is  a  modification  of  that  previously  adopted  in  America.  The 
latter  differs  from  the  B.P.  process  chiefly  in  prescribing  the  use 
of  a  larger  proportion  of  ammonium  chloride.  This  is  a  distinct 
disadvantage  as  tending  to  retain  morphine  in  solution,  a  fact 
pointed  out  by  M.  Conroy,  and  confirmed  by  Wram- 
pelmeier  and  Meinert.^ 

Method  of  Teschemacher  and  Denham  Smith. — These  chemists 
have  examined  most  of  the  published  methods  of  assaying  opium 
(Chem.  Neivs,  Ivii.  93,  103),  and  have  found  them  wanting  in  one 
or  more  respects.  They  reject  methods  in  which  the  precipitation 
of  the  morphine  is  effected  in  presence  of  more  than  a  very  limited 
amount  of  alcohol  (e.g.,  Fluckiger's  older  methods)  as  likely  to 
yield  low  results,  though  a  very  pure  product ;  they  object  to  the 
use  of  lime  (as  in  the  B.P.  product)  as  causing  the  product  to  be 
coloured,  and  being  open  to  other  objections ;  and  they  strongly 
advocate  the  titration  of  the  morphine  isolated, instead  of  determining 
it  gravimetrically.  All  these  objections  are  well  founded,  though 
scarcely  so  vital  as  they  are  regarded  by  the  authors,  who,  however, 
have  described  a  method  of  assay  which,  on  the  whole,  is  probably 
the   best   hitherto   published.^     The    process   they  recommend  is 

*  These  latter  chemists  calculated  the  amount  of  ammonium  chloride  which 
would  remain  in  excess,  and  free  ammonia  which  would  be  produced  in  the 
reaction,  and  ascertained  their  solvent  action  on  morphine  ;  but  the  correction 
logically  based  on  their  results  would  be  seriously  in  excess  of  the  actual  loss 
of  morphine  in  practice.  H.  Lloyd  has  proposed  to  correct  the  results  ob- 
tained by  the  U.S.  process  by  adding  5  per  cent,  to  the  amount  of  morphine 
(or  multiplying  it  by  1*05),  and  making  an  additional  correction  of  1  per  cent, 
to  the  morphine  thus  found.  Thus,  if  9'0  per  cent,  of  morphine  be  actually 
recovered,  according  to  H.  Lloyd,  the  true  amount  present  is  9*0  x  1 '05 +  1*0 
=  10 "45  per  cent.  Similarly,  H.  Goebel  {Jour.  Chem.  Soc,  lii.  869)  re- 
commends an  allowance  of  O'OOl  giamme  for  each  c.c.  of  liquor  and  washing, 
and  points  out  certain  defects  in  the  U.S.  process  which  may  be  overcome  by 
modified  manipulation. 

2  This  view  is  confirmed  by  D.  B.  Dott,  who  operates  as  follows  : — 10 
grammes  weight  of  the  powdered  opium  is  exhausted  with  proof  spirit,  one  or 
two  drops  of  ammonium  oxalate  are  added,  and  then  ammonia,  until  the  spirit 
is  only  slightly  acid.     The  liquid  is  then  evaporated  to  one-third,  allowed  to 


348  ASSAY  OF  OPIUM. 

founded  on  one  originally  devised  by  P  r  o  1 1  i  u  s  and  modified  by 
r.  A.  Fliickiger  (Archiv.  der  Pliarm.,  [3],  xxvi.).  It  was  then 
materially  improved  by  E.  R.  Squibb  (Ephemeris,  i.  14),  and 
again  further  modified  by  C.  M.  Still  well  (Chem.  News,  Iv. 
41,  54).  The  following  are  the  details  of  the  process  as  prescribed 
by  Teschemacher  and  Smith : — 200  grains  weight  of  opium  is 
thoroughly  exhausted  with  warm  distilled  water,  ^  and  the  liquid 
filtered.  The  aqueous  extract  is  concentrated  to  a  thin  syrup  in  a 
shallow  dish,  over  a  water-bath,  which  by  preference  should  not 
boil.  The  syrup  is  transferred  to  a  suitable  flask,  and  the  dish 
washed  out  with  a  few  drops  of  water.  To  the  contents  of  the 
flask  are  added  50  fluid  grains  of  alcohol  (specific  gravity  '820) 
and  about  600  fluid  grains  of  ether.  A  soft  cork  is  inserted  and 
the  contents  of  the  flask  mixed  gently  but  thoroughly,  after  which 
50  fluid  grains  of  ammonia  (specific  gravity  "935)  should  be  added. 
The  flask  is  then  well  shaken  to  precipitate  the  alkaloid  in  arena- 
ceous crystals,  and  occasionally  agitated  during  the  ensuing  eighteen 
hours.  The  contents  of  the  flask  are  then  transferred  to  a  vacuum- 
filter,  and  when  all  the  adherent  liquid  is  drawn  out  the  crystalline 
precipitate  is  washed  with  "  morphiated  spirit "  ^  until  the  liquid 
passes  through  colourless.  It  is  then  washed  with  *'  morphiated 
water  "  ^  until  this  also  passes  colourless.  The  precipitate  is  then 
dried,  at  first  slowly  and  afterwards  at  100°  C.  The  dried  sub- 
stance is  then  finely  powdered  and  digested  thoroughly  in  benzene 
to  dissolve  the  narcotine  and  such  other  opium  alkaloids  as  may  be 
present  in  addition  to  morphine.^     The  liquid  is  filtered  and  the 

cool,  and  filtered.  The  filtrate  is  concentrated  to  about  5  c.c,  transferred  to 
a  small  flask,  and  the  capsule  washed  with  4  c.c.  of  water  and  3  of  methylated 
spirit.  Next  add  2*2  c.c.  of  ammonia  solution  (sp.  gr.  'OGO)  and  25  c.c.  of 
ether,  and  agitate.  After  18  hours,  decant  tlie  ether  as  completely  as  possible, 
receive  the  aqueous  liquid  on  a  counterpoised  filter,  wash  with  morphiated 
water,  dry,  wash  with  benzene,  dry,  weigh,  and  titrate  the  whole  or  a  portion 
with  decinormal  sulphuric  acid  {Fharm.  Jour.,  [3],  xxii.  746), 

^  Rowland  "Williams  digests  with  cold  water  for  twelve  to  fourteen,  hours, 
and  claims  to  obtain  a  cleaner  solution  than  when  warm  water  is  used. 

2  The  ^^ Morphiated  Spirit"  is  made  by  mixing  1  measure  of  ammonia 
(specific  gravity  '880)  with  20  of  methylated  spirit,  and  digesting  in  the  liquid 
a  large  excess  of  powdered  morphine  for  several  days,  with  frequent  agitation. 
The  filtered  liquid  contains  0*33  per  cent,  of  morphia.  "Morphiated  Water" 
is  made  by  agitating  cold  water  with  excess  of  morphine,  and  filtering  after 
twenty-four  hours.     The  filtrate  contains  0"04  per  cent,  of  alkaloid. 

3  Seeing  that  the  morphine  is  ultimately  determined  by  titration,  that  nar- 
cotine, narceine,  and  papaverine  have  no  action  on  litmus,  and  that  codeine 
is  soluble  in  80  parts  of  cold  water  and  readily  soluble  in  alcohol  and  ether, 
the  prescribed  treatment  with  benzene  in  order  to  remove  these  alkaloids 
seems  superfluous.     When  the  morphine  is  to  be  weighed,  it  would  probably 


MORPHIOMETRY.  349 

precipitate  further  thoroughly  washed  with  benzene.  The  residue 
will  consist  of  morphine  "  free  from  other  opium  alkaloids  and 
narcotine,  but  still  containing  colouring  and  possibly  other 
organic  matters  to  the  extent  of  3  to  10  per  cent."  (of  its  weight). 
The  powder  is  dried,  weighed,  and  titrated  with  litmus  and  a 
standard  hydrochloric  acid,  prepared  so  that  1000  grains  by 
weight  will  exactly  neutralise  100  grains  of  pure  morphine  crystal- 
lised from  water,  washed  with  ether,  and  gently  dried  at  100°  C. 
Fluckigers  process.  F.  A.  Fliickiger  has  devoted  much  attention 
to  the  assay  of  opium,  his  most  recent  method  (Archlv.  Pharm., 
[3],  xxvii.  721,  769  ;  Fharm.  Jour.,  [3],xx.  588)  being  as  follows  : 
— 8  grammes  weight  of  powdered  opium  is  placed  in  a  plaited  filter, 
and  dried  at  100°  for  half  an  hour.  It  is  then  treated  with  20  c.c. 
of  a  mixture  of  equal  measures  of  ether  and  chloroform,  and  when 
this  has  run  through,  with  10  c.c.  of  unmixed  chloroform.  The 
filter  and  its  contents  are  then  dried  at  a  gentle  heat,  and  the 
powder  vigorously  and  repeatedly  shaken  in  a  flask  with  80  c.c. 
of  water  to  which  0'2  gramme  of  ammonium  oxalate  has  been 
added.  After  two  hours  the  liquid  is  passed  through  a  dry  filter, 
and  42*5  grammes  of  the  filtrate  (  =  4  grammes  of  sample)  treated 
in  a  small  tared  flask  with  7  J  c.c.  of  rectified  spirit,  15  c.c.  of 
ether,  and  1  c.c.  of  ammonia  (specific  gravity  0'96).  The  mixture 
is  frequently  shaken  during  six  hours,  after  which  the  liquid  is 
poured  on  a  double  filter,  the  flask  rinsed  with  10  c.c.  of  water  or 
morphiated  water,  and  the  rinsing  used  to  wash  the  filter.  The 
precipitate  and  inner  filter  are  dried  at  100°,  returned  to  the  dried 
flask,  and  the  whole  further  heated  to  100°  till  constant,  the  outer 
filter  being  used  as  a  counterpoise.  The  foregoing  process  would 
be  materially  improved  and  shortened  by  titrating  the  dried  mor- 
phine instead  of  weighing  it  on  a  counterpoised  filter,  and  its 
accuracy  increased  by  reducing  the  quantities  of  liquid  used.  J.  B. 
Nagelvoort  {Pharm.  Jour.,  [3],  xxi.  598)  has  slightly  modi- 
fied the  above  method,  which  he  commends  very  highly,  for 
the  assay  alike  of  opium  and  its  galenical  preparations.  He  found 
the  isolated  alkaloid  to  be  completely  soluble  in  100  parts  of 
lime-water  to  a  clear,  colourless  solution,  whereas  the  "  morphine  " 
obtained  by  Squibb's  and  Stillwell's  modifications  of  Flilckiger's 
former  process  contained  from  10  to  20  per  cent,  of  impurities.-^ 

be  better  to  wash  with  morphiated  spirit  only,  and  when  it  is  to  be  titrated  to 
omit  this  treatment  and  wash  it  at  once  with  benzene. 

1  If  narcotine  be  present  it  is  left  as  a  crystalline  residue  on  treating  the 
alkaloid  with  lime-water.  Perger  has  proposed  to  purify  morphine  by  dis- 
solving it  with  dilute  acetic  acid  and  adding  potassium  ferrocyanide,  filtering, 
and  precipitating  the  morphine  from  the  filtrate  by  ammonia. 


350  EXTKACT  OF  OPIUM. 

L.  Kieffer,  in  1857,  described  a  volumetric  process  of 
assaying  opium,  based  on  the  reaction  of  the  morphine  with 
potassium  feiricyanide,  reaction  of  the  excess  of  this  salt  with 
potassium  iodide,  and  titration  of  the  liberated  iodine  with  standard 
thiosulphate  (Annal.  Cliem.  Pharm.y  ciii.  280).  A  limited  number 
of  experiments  made  in  the  author's  laboratory  on  Kieffer's  process 
have  not  yielded  encouraging  results. 

Extract  of  Opium,  B.P.,  is  made  by  exhausting  the  opium 
with  cold  water,  straining,  and  evaporating  the  liquid  to  half  the 
weight  of  the  opium  used.  It  has  a  pilular  consistency,^  and  is 
said  to  yield  about  20  per  cent,  of  morphine  when  assayed  by  the 
official  test  for  opium.  W.  P.  Want  {Pharm.  Jour.,  [3],  xvi. 
959)  found  by  this  process  from  9*9  to  20*4  per  cent,  of  mor- 
phine in  six  samples  of  the  commercial  extract  of  opium.^ 
By  the  method  of  the  1867  Pharmacopoeia,  D.  B.  Dott  found 
in  eleven  samples  of  extract,  purchased  from  druggists  of  good 
standing  in  London,  Dublin  and  Edinburgh,  proportions  of 
morphine  ranging  from  15"4  to  22'8  per  cent.,  the  mean  being 
19-7. 

Liquid  Extract  of  Opium,  B.P.,  is  prepared  by  macerating 
1  ounce  of  the  solid  extract  with  1 6  ounces  of  water,  adding  4  jBiuid 
ounces  of  rectified  spirit,  and  filtering.  It  should  contain  "22 
grains  of  the  solid  extract  in  nearly  1  fluid  ounce."  The  specific 
gravity  should  be  between  0*985  and  0*995,  and  when  assayed  by 
the  process  prescribed  for  opium  "  should  yield  about  1  per  cent,  of 
morphine." 

J.  Woodland  {Year-Book Pharm.,  1882,  p.  514)  found  in  ten 
samples  of  the  liquid  extract  of  opium  of  commerce  proportions  of 
soKd  residue  ranging  from  3*02  to  4"92  per  cent.,  and  of  mor- 
phine from  0'19  to  0'37  per  cent.  These  determinations  were 
made  by  a  modification  of  ProUius'  method,  the  accuracy  of 
which  was  demonstrated.  D.  B.  Dott  {Year-Booh  Pharm., 
1876,  500)  found  the  specific  gravity  of  eleven  samples  of 
commercial  fluid  extract  to  range  from  0*985  to  TO 00,  while 
the  proportion  of  morphine  per  fluid  ounce  varied  from  1*66  to 
4*51  grains. 

Tincture  OF  Opium.  Laudanum.  For  the  preparation  of  this  im- 
portant medicine,  the  British  Pharmacopoeia  directs  to  "  macerate 
1^   ounces   of    opium    in    powder  in    1  pint    of    proof   spirit  for 

^  The  United  States  Pharmacopoeia  orders  an  addition  of  5  per  cent,  of 
glycerin. 

'  J.  H.  Hoseason  {Pharm.  Jour.,  [3],  xix.  754)  has  pointed  out  that 
extract  of  opium  is  sold  by  wholesale  druggists  at  a  cheaper  rate  than  they  can 
purchase  the  opium  for  its  preparation. 


TINCTUKE   OF  OPIUM.  351 

seven  days  in  a  closed  vessel  with  occasional  agitation,  then  strain, 
press,  filter,  and  add  sufficient  proof  spirit  to  make  one  pint.  It 
contains  the  soluble  matter  of  33  grains  of  the  opium,  nearly,  in 
1  fluid  ounce,  or  about  3*3  grains  of  morphine  in  1  fluid  ounce,  or 
about  0*75  per  cent,  of  morphine,  or  about  IJ  per  cent,  of  bime- 
conate  of  morphine,  ^  besides  the  other  alkaloidal  salts  of  opium."  ^ 
No  specific  gravity  is  given,  and  no  method  of  testing  the  pre- 
paration is  })rescribed ;  but  it  is  evident  that  the  method  employed 
for  the  assay  of  opium  may  be  applied,  after  evaporating  ofl"  the 
spirit. 

W.  P.  Want  {Pharm.  Jour.,  [3],  xvi.  959)  found  the  specific 
gravity  of  six  samples  of  tincture  of  opium  procured  from  leading 
wholesale  houses  to  range  from  '931  to  '939.  The.  proportions  of 
morphine  were  estimated  (in  duplicate)  by  the  official  process  for 
opium  (using  about  3  ounces  of  the  tincture),  and  were  found  to 
be  respectively :— 3-34,  3*3,  2-6,  3-3,  3-4,  and  2-18  grains  per 
fluid  ounce.  All  six  samples  were  very  similar  in  appearance  and 
odour. 

J.  H.  Hoseason  (Pharm.  Jour.,  [3],  xix.  754)  has  published 
the  following  results  of  the  examination  of  ordinary  commercial 
samples  of  tincture  of  opium  : — 

1  This  statement  of  the  condition  of  existence  of  the  morphine  is  without 
warrant,  and  is  opposed  to  the  known  facts.  The  very  existence  of  '*  bime- 
conate  of  morphine  "  is  doubtful,  and  a  large  proportion  of  the  morphine  in 
opium  exists  as  sulphate. 

2  The  Tinctura  Opii  of  the  United  States  Pharmacopoeia  (1882)  is 
prepared  from  powdered  opium  (assaying  12  to  16  per  cent,  of  morphine)  10 
parts,  water  40  parts,  alcohol  (specific  gravity  '820)  16  parts,  and  sufficient 
dilute  alcohol  (specific  gravity  "928)  to  make  the  tincture  obtained  by  percola- 
tion up  to  100  parts.     All  the  ingredients  are  by  weight. 

The  Tinctura  Opii  Simplex  of  the  German  Pharmacopoeia  (1890)  is 
prepared  from  powdered  opium  (with  10  per  cent,  or  more  of  morphine)  1  part, 
diluted  alcohol  (specific  gravity  -892  to  '896  at  15°  C.)  5  parts  by  weight,  and 
water  5  parts.  It  has  a  specific  gravity  of  '974  to  '978,  and  contains,  in  100 
grammes,  the  soluble  portion  of  nearly  10  grammes  of  o[)ium,  or  approximately 
1  per  cent,  of  morphine.  40  grammes  when  assayed  should  yield  not  less  than 
0'38  gramme  of  morphine. 

The  corresponding  preparation  {Tinctura  Extractce  Opii)  oi  the  French 
Codex  (1884)  is  prepared  from  10  parts  of  extract  of  opium  (  =  167  of  dry 
opium)  containing  10  to  12  per  cent,  of  morphine,  and  120  parts  by  weight  of 
alcohol  of  '912  specific  gravity. 

From  these  particulars  it  is  evident  that  the  strength  of  the  official 
tinctures  of  opium  vary  considerably,  both  in  alcoholic  strength  and  the 
proportion  of  morphine.  The  United  States  and  French  preparations  are 
the  strongest  (in  alkaloid),  the  German  weaker,  and  the  British  the  most 
dilute. 


352 


TINCTURE  OF   OPIUM. 


Number. 

Specific  Gravity. 

Absolute 

Alcohol;  per 

cent,  by  weight. 

Residue ;  grs. 
per  fluid  ounce. 

Morphine ; 

grs.  per  fluid 

ounce. 

1 
2 
3 

5 

? 

8 
9 
10 

•964 
•952 
•942 
•940 
•962 
•960 
•961 
•966 
•961 
•946 

38 
40 
41 
42 
36 
37 
37 
35 
38 
40 

18-5 
17-0 
20^5 
145 
153 
17  •S 
15-0 
13^5 
14-6 
18^0 

3-5 
30 
5^0 
2  0 
2^0 
3-0 
2-0 
2^5 
2-7 
3^0 

j  Average,    .    . 

•955 

38^4 

1 

16^4 

2^8 

Six  of  the  above  samples  were  evidently  made  with  a  mixture 
of  equal  measures  of  rectified  spirit  and  water,  instead  of  the 
proportion  of  6  :  3,  which  would  yield  approximately  proof-spirit. 

J.  Woodland  {Year-Book  Pharm.^  1882,  page  514)  found 
the  solid  residue  from  fourteen  samples  of  tincture  of  opium  pro- 
cured from  both  London  and  provincial  chemists  to  range  from 
3*21  to  5'11  per  cent. ;  while  the  morphine  (estimated  by  a  modi- 
fication of  Proliius'  method)  ranged  from  0*32  to  0"70  psr  cent. 

D.  B.  Dott  {Year-Book  Pharm.,  1876,  page  500)  found  the 
specific  gravity  of  twelve  samples  of  the  commercial  tincture  of 
opium  to  range  from  "922  to  -962;  while  the  crude  morphine 
(estimated  by  a  modification  of  the  B.P.  1867  method,  and 
averaging  ^^  of  pure  alkaloid)  contained  in  the  same  specimens, 
and  six  others  (the  density  of  which  was  not  observed),  ranged 
from  4*37  to  0*55  grains  per  fluid  ounce,  the  average  being 
2-66. 

From  the  foregoing  published  results  it  is  evident  that  the 
composition  of  commercial  tincture  of  opium  varies  to  a  very 
discreditable  extent,  both  in  alcoholic  strength  and  the  proportion 
of  morphine  contained  in  it.  Still  greater  variations  in  strength 
are  to  be  found  in  the  tincture  when  purchased  under  the  head 
of  "laudanum,"  which,  however,  is  now  an  official  synonym  for 
tincture  of  opium.^ 

S.  J.  Hinsdale  {Chem.  News,  Ixii.  77)  has  described  a  simple 

^  Several  prosecutions  have  occurred  under  the  Sale  of  Food  and  Drugs  Act 
for  the  sale  of  defective  tincture  of  opium.  In  the  case  of  White  v.  By  water, 
it  was  sold  under  the  official  name  to  the  written  order  of  a  medical  man. 
The  court  accepted  the  view  of  the  defence,  that,  as  the  preparation  con- 
tained alcohol,  it  was  a  "tincture,"  and  that  if  it  contained  any  opium  at 
all  it  was  a  "tincture  of  opium,"  which,  consequently,  might  be  of  any 
strength  whatever.  This  decision  was  reversed  on  appeal  to  the  Court  of 
Queen's  Bench  {Fharm.  Jour.,  [3],  xvii.  966). 


COMPOUND  TINCTURE   OF   CAMPHOR.  353 

method  of  determining  the  morphine  in  tincture  of  opium  by 
observing  the  depth  of  the  blue  or  green  coloration  produced  on 
treating  the  sample  with  a  freshly  prepared  mixture  of  ferric 
chloride  and  potassium  ferricyanide  solutions. 

Compound  Tincture  of  Camphor,  B.P.,  is  the  formal  designa- 
tion of  the  preparation  popularly  known  as  "Paregoric,"  or 
"Paregoric  Elixi r."  These  names  were  adopted  as  official 
synonyms  for  compound  tincture  of  camphor  in  the  reprint  of  the 
British  Pharmacopoeia  of  1886,  and  hence  preparations  sold 
under  these  titles  ought  now  to  be  strictly  of  the  quality  and 
strength  of  the  B.P.  tincture.  Compound  tincture  of  camphor 
is  directed  to  be  prepared  with  40  grains  each  of  opium  and 
benzoic  acid,  30  grains  of  camphor,  and  30  minims  of  oil 
of  anise ;  the  whole  being  diluted  with  proof -spirit  to  20  fluid 
ounces.^ 

Much  of  the  paregoric  or  compound  tincture  of  camphor  of 
commerce  is  deficient  in  one  or  more  of  the  constituents.  The 
spirit  being  the  most  costly  ingredient,  there  is  a  strong  induce- 
ment to  the  vendor  to  reduce  its  amount,  a  practice  which  is 
objectionable  because  the  prescribed  proportion  of  oil  of  anise 
cannot  be  kept  in  solution  in  a  very  weak  spirit.  Sometimes 
only  traces  of  oil  of  anise  are  present,  in  which  case  the  tincture 
remains  clear  when  diluted  with  three  or  four  measures  of  water. 
The  benzoic  acid  is  sometimes  deficient  in  quantity,  and  occa- 
sionally wholly  absent,  even  in  the  case  of  tinctures  purchased 
from  registered  i)harmacists.  The  opium  is  the  most  important 
constituent  of  paregoric  elixir,  and  is  apt  to  be  deficient  in  amount 
or  quality,  besides  being  frequently  wholly  omitted.  The  last 
practice  is  due  to  the  fact  that  preparations  of  opium  cannot  be 
legally  sold  except  by  registered  pharmacists ;  and  hence  a  prepara- 
tion destitute  of  opium  is  largely  substituted  by  general  shop- 
keepers for  the  genuine  "  paregoric "  or  "  compound  tincture  of 
camphor"  sold  by  the  druggists.^  In  an  instance  within  the 
personal  experience  of  the  author,  the  opium  of  paregoric  elixir  was 
replaced  by  henbane.  Potassium  and  ammonium  bromides, 
are  extensively  used  in  factitious  paregoric. 

The  proportion  of  alcohol  in  compound  tincture  of  camphor  is 

1  W.  D.  Mason  {TJiartn.  Jour.,  [3],  xii.  396)  points  out  that  great  saving 
of  time  and  trouble  in  maceration,  agitation,  filtering,  &c.,  could  be 
effected,  and  a  perfectly  clear  and  bright  tincture,  practically  the  same  as 
that  of  the  Pharmacopoeia,  obtained  by  adding  the  opium  in  the  form  of  a 
ready-made  tincture 

2  So-called  "paregoric"  is  vended  by  costermongers  in  the  streets  of 
London. 

VOL.   III.   PART  II.  Z 


.'354  .  ANALYSIS  OF   PAREGORIC. 

indicated  with  approximate  accuracy  by  the  specific  gravity,  which 
should  not  be  higher  than  092  6.^ 

.  If  a  measured  quantity  (25  c.c.)  of  paregoric  be  rendered 
distinctly  alkaline  with  soda,  and  evaporated  to  about  10  c.c, 
the  alcohol  and  a  portion  of  the  camphor  and  oil  of  anise  will  be 
volatilised.  On  then  shaking  the  liquid  with  ether,  the  remaining 
camphor  and  oil  of  anise  will  be  extracted.  If  the  ether  be 
separated,  and  the  aqueous  liquid  acidulated  with  hydrochloric 
acid,  benzoic  acid  will  in  some  cases  be  precipitated ;  but  whether 
it  separates  or  remains  in  solution,  it  should  be  dissolved  out  by 
agitating  the  acidified  liquid  with  ether.  On  allowing  the  separated 
ethereal  solution  to  evaporate  spontaneously  in  a  small  beaker,  the 
benzoic  acid  is  obtained  in  a  state  fit  to  weigh  -^  but  a  better  and 
more  rapid  plan  is  to  repeatedly  agitate  the  ethereal  liquid  with 
water  until  the  washings  no  longer  redden  litmus,  add  a  little 
more  water  and  a  few  drops  of  phenolphthalein  solution,  and 
titrate  the  liquid  with  -^  caustic  alkali  (preferably  baryta-water), 
which  should  be  added  until  the  aqueous  layer  acquires  a  pink 
colour,  not  destroyed  by  agitation  with  the  ether.  Each  1  c.c.  of 
-^  alkali  required  represents  O'OOGl  gramme  of  benzoic  acid.  If 
25  c.c.  of  the  tincture  has  been  employed,  the  number  of  milli- 
grammes of  benzoic  acid  found,  multiplied  by  0*35,  gives  the 
grains  of  benzoic  acid  per  pint  of  the  tincture.  The  meconic 
acid  extracted  together  with  the  benzoic  acid  is  too  small  in 
quantity  to  affect  the  result,  but  its  presence  may  be  detected 
and  the  amount  roughly  determined  by  separating  the  ethereal 
layer  after  the  titration  is  complete,  and  destroying  the  pink 
colour  of  the  aqueous  liquid  by  a  drop  of  dilute  hydrochloric 
acid.  On  now  adding  a  drop  of  ferric  chloride  solution,  the  deep 
purple-red  coloration  characteristic  of  meconic  acid  will  be  produced. 
The  detection  of  meconic  acid  in  the  above  manner  of  course 
proves  the  presence  of  opium  in  the  tincture.  When  this  infor- 
mation alone  is  sought,  the  paregoric  may  be  diluted  in  a  test-tube 
with  proof-spirit  till  it  is  of  a  light  yellow  colour,  and  a  drop  or 
two  of  solution  of  ferric  chloride  then  added.  If  opium  be  present, 
more  or  less  deep  red  coloration  will  be  produced,  owing  to  the 
formation  of  meconate  of  iron.  By  comparing  the  depth  of  red 
colour  with  that  given  by  a  standard  tincture,  a  rough  indication 
of  the  proportion  of  opium  present  can  be  obtained ;  but  the 
amount  of  meconic  acid  in  opium  is  too  variable  to  allow  of  much 

1  Where  a  more  exact  determinatiou  is  required,  it  may  be  made  by  the 
method  described  in  Volume  I.,  under  the  head  of  Tinctures. 

2  The  author  has  occasionally  observed  the  benzoic  acid  thus  extracted  to 
have  a  distinct  urinous  odour. 


PHYSIOLOGICAL   EFFECTS  OF,  OPIUM.  355 

stress  being  placed  on  the  result  obtained.  It  sometimes  happens 
that  paregoric  is  coloured  with  cochineal  or  contains  a  variety  of 
tannin,  in  which  case  the  coloration  with  ferric  chloride  becomes 
obscured.  On  cautiously  adding  hydrochloric  acid,  drop  by  drop, 
the  colour  produced  by  tannate  of  iron  is  destroyed,  while  that  due 
to  the  meconate  persists  till  considerably  more  acid  has  been  added. 
The  proportion  of  opium  in  paregoric  is  too  small  to  allow  of 
the  ordinary  method  of  determining  morphine  being  conveniently 
used  j  but  fair  results,  sufficiently  accurate  for  most  purposes,  may 
be  obtained  by  volumetric  or  colorimetric  application  of  the 
reactions  with  potassium  ferricyanide  and  iodic  acid  (pages  317,  318). 

Toxicology  of  Opium  and  Morphine. 

In  whatever  form  or  manner  it  may  be  administered,  opium  is 
found  to  act  as  a  typical  and  powerful  narcotic,  and  in  excessive 
doses  is  fatally  poisonous.^ 

^  In  a  letter  to  tlie  Globe,  D  r  W  m.  Moore,  late  Surgeon-General,  Bombay, 
points  out  the  exaggerated  statements  made  respecting  the  ill  effects  of  opium 
eating  and  smoking.  He  writes  : — **  No  one  denies  that  the  excessive  use  of 
opium — whether  smoked,  eaten,  or  drunk — produces  injurious  consequences  ; 

but  so  does  excess  in  the  use  of  spirits,  of  roast  goose,  or  even  of  fruit 

I  am  quite  sure  that  the  use  of  opium,  speaking  generally,  is  more  advan- 
tageous than  deleterious.  Anti-opiumists  assert  that  all  using  the  drug  in  any 
form  go  from  bad  to  worse,  and  eventually  succumb  to  the  effects.  This  is  not 
the  fact.  There  are  thousands  who  use  opium  moderately  from  their  youth 
upwards,  and  never  suffer  therefrom.  That  the  habit  cannot  be  given  up  is 
also  incorrect.  But,  as  a  matter  of  fact,  immoderate  consumers  are  like  drink- 
era  vers,  and  rarely  give  up  the  habit.  And  moderate  consumers  do  not  do  so, 
finding  that  it  does  not  work  them  harm. 

** The  use  of  opium,  even  in  excess,  is  neither  so  deleterious  to  the 

consumer  nor  so  dangerous  to  his  neighbours  as  the  use  of  spirits  to  excess. 

The  opium  eater  or  smoker attains  to  a  placid  repose,  which  is  very 

different  to  the  excitement  caused  by  spirits Many  maladies  for  which 

opium  is  used  in  the  East  have  been  attributed  to  opium.  Numbers  of  people 
suffering  from  all  kinds  of  maladies  are  to  be  found  in  Eastern  opium-houses. 
But  the  people  thus  affected  fly  to  opium  for  a  relief  to  suffering,  and  visitors 
finding  diseased  people  in  the  opium-houses  have  ignorantly  attributed  the 

maladies  seen  to  the  use  of  opium Opium  prevents  eremacausis  or 

waste  of  tisue,  and  thus  contributes  to  endurance  of  fatigue,  as  evidenced  by 
the  long  distances  Kossids  travel  in  India,  their  only  support  being  a  small 
pill  of  opium,  a  number  of  which  they  carry  in  a  tin  box.  This  is  evidenced 
also  by  opium  being  given  to  camels,  in  combination  with  other  substances, 
when  these  animals  are  called  upon  for  extraordinary  exertions.  Opium  also 
enables  persons  to  live  on  smaller  quantities  of  food  than  they  could  otherwise 
do — in  this  resjject  it  resembles  tea.  Thousands  were  kept  alive  during  Indian 
famines  who  would  have  succumbed  from  want  of  food  had  not  opium  been 
availabl?. There  is  also  no  doubt  that  opium  exerts  si  prophylactic 


356  POISONING  BY  OPIUM. 

The  poisonous  effects  of  opium  are  essentially  due  to  the  mor- 
phine contained  in  it,  and  the  symptoms  it  produces  differ  but  little 
from  those  consequent  on  the  administration  of  pure  morphine, 
except  that  there  is  a  greater  tendency  to  convulsions,  and  in  the 
latter  case  the  effects  are  usually  manifested  more  rapidly  than  in  the 
former,  generally  commencing  in  from  five  to  twenty  minutes  if  the 
poison  has  been  taken  in  solution. 

After  poisoning  by  morphine  or  opium,  dimness  of  sight  and 
relaxation  of  the  muscles,  with  drowsiness  and  stupor,  are  usually 
the  first  symptoms  observed.  At  first  the  patient  may  be  aroused 
without  much  difficulty,  but  as  time  goes  on  this  becomes  impos- 
sible, the  drowsiness  passing  into  complete  coma,  often  accompanied 
by  slow  and  stertorous  breathing,  ending  in  death.  In  the  large 
majority  of  cases  the  pupils  are  strongly  contracted  in  the  earlier 
stages ;  but  later,  and  when  a  fatal  termination  is  approaching, 
they  are  often  dilated.^  They  are  usually  insensible  to  light. 
Occasionally,  especially  with  excessive  doses  of  opium,  there  is 
vomiting,  or  even  purging.  The  pulse  is  at  first  weak,  quick,  and 
irregular,  but  afterwards  slow  and  full. 

Poisoning  by  morphine  or  opium  often  closely  simulates  alcoholic 
drunkenness,  and,  in  the  absence  of  a  smell  of  opium  in  the  breath 
or  vomit,  it  is  often  very  difficult  to  distinguish  between  them. 
Coma,  due  to  uraemia,  apoplexy,  or  violence,  may  also  be  mistaken 
for  poisoning  by  opium  or  its  preparations. 

The  dose  of  morphine  necessary  to  destroy  life  is  extremely 
variable.  Infants  ai.d  young  persons  are  peculiarly  susceptible  to 
opium  and  its  preparations.     Death  has  been  caused  to  infants  by 

effect  against  malarious  fevers,  which  eflFect  is  recognised,  not  only  in  the  East, 
but  also  in  the  aguish  districts  of  this  country.  That  it  relieves  chronic 
painful  malalies  does  not  require  proof. 

" People  in  the  East  will  have  opium — for  with  them  it  takes  the 

place  of  other  stimulants  or  narcotics — and  they  will  have  it  in  spite  of  any- 
thing anti-opiumists  may  advance  to  the  contrary In  opium  they 

have  a  cheap,  easily  carried  stimulant  or  narcotic,  according  as  they  may  use 
it,  and  nothing  the  anti-opiumists  may  say  will  prevent  the  use  of  opium. 
Eating  opium  is  more  deleterious  than  smoking  the  drug,  for  it  interferes  more 
with  the  digestive  capacities.  Taking  opium  in  the  form  of  opium  water 
{umal  pavjnee)  is  less  injurious.  Smoking  opium  is  the  least  harmful  manner 
of  using  the  drug.  It  is  not  opium  that  is  used  for  smoking,  but  a  preparation 
of  opium  called  chandul  or  chandoo  ;  and,  after  much  experience  and  investi- 
gation, I  regard  smoking  chandul  as  harmless,  unless  indulged  in  to  excess. 
And  the  vast  majority  of  those  using  chandul  do  not,  like  the  vast  majority  of 
hhose  using  spirits,  proceed  to  excess. — 15  Portland  Place,  March  10,  1891." 

^  A.  Swaine  Taylor  mentions  a  case  of  opium  poisoning  in  which  one 
pupil  was  contracted  and  the  other  dilated. 


POISONING  BY   OPIATES.  357 

Jth,  -j^jth,  i^th,  and  even  j^tli  of  a  grain  of  opium ;  as  also  by  a 
few  drops,  and  even  a  single  drop,  of  tincture  of  opium.  On  the 
other  hand,  children  have  recovered  after  doses  of  1  grain,  5  grains, 
and  7  J  grains  of  opium,  and  after  two  teaspoonfuls  of  laudanum. 
Half  a  grain  of  morphine  acetate  has  proved  fatal  to  an  adult ;  but 
as  a  rule,  the  usual  minimum  fatal  dose  for  an  adult  may  be  stated 
as  1  grain  of  a  salt  of  morphine,  or  7  grains  of  opium.  Personal 
habit,  as  in  the  case  of  opium-eaters,  and  idiosyncrasy  will  of 
course  largely  modify  the  above  conclusion. 

The  post-mortem  appearances  of  poisoning  by  morj^hine  are  by 
no  means  well-marked.  The  stomach  and  intestines  usually 
appear  healthy.  If  opium  itself  has  been  taken,  its  peculiar  and 
characteristic  odour  may  often  be  recognised  when  the  stomach  is 
first  opened.^  Congestion  of  the  lungs  and  brain  are  most  com- 
monly met  with ;  but  these  appearances  are  not  invariable,  and 
when  they  exist,  afford  no  definite  evidence  of  opium  poisoning. 
The  blood  is  usually  very  fiuid. 

Besides  opium  itself,  morphine  and  its  salts,  and  the  various 
official  preparations  of  opium  {e.g.,  the  tincture  and  extract),  there  are 
various  nostrums  containing  opium,  which  have  not  unfrequently 
been  the  cause  of  death  ;  especially  in  the  case  of  infants,  for  whom 
opiates  may  be  regarded  as  generally  dangerous  and  unsuitable.^ 

^  The  author  has  observed  an  unmistakable  smell  of  opium  in  the  contents 
of  the  bladder  sixty  hours  after  death  by  taking  laudanum. 

2  Syrup  of  Poppies  is  professedly  a  sweetened  decoction  of  English  or  white 
poppy  heads.  It  is  of  very  variable  strength,  and  is  said  to  be  sometimes 
substituted  by  a  mixture  of  tincture  or  infusion  of  opium  with  simple  syrup. 

TFinslow's  Soothing  Syrup  sometimes  produces  symptoms  of  narcotic  poison- 
ing. It  is  said  to  contain  about  1  grain  of  morphine  and  other  opium  alka- 
loids in  an  ounce  {Pharm.  Jour.,  [3],  ii.  975). 

Godfrey's  Cordial  is  stated  to  be  a  mixture  of  treacle  and  sassafras  with  1 
drachm  of  tincture  of  opium  in  6  ounces.  Half  a  teaspooiiful  is  said  to  have 
caused  the  death  of  an  infant;  and  in  the  years  1863-67,  fifty-six  deaths  were 
recorded  from  its  use,  probably  by  its  administration  in  excessive  doses  by  igno- 
rant persons. 

HawksworMs  Mixture  contains  magnesium  carbonate,  rhubarb,  compound 
spirits  of  ammonia,  sweet  spirit  of  nitre,  oil  of  cassia,  simple  syrup,  water,  and 
other  ingredients,  with  1  part  of  tincture  of  opium  in  54. 

Chlorodyne  is  a  preparation  of  variable  character,  containing  chloroform,  ether, 
alcohol,  oil  of  peppermint,  hydrocyanic  acid,  treacle,  and  morphine  hydrochlo-. 
ride.   Lobelia,  capsicum,  belladonna,  and  extract  of  liquoriceare  sometimes  added 

Paregoric  Elixir  is  the  popular  name  for  the  compound  tincture  of  camphor, 
B.  P.  Various  preparations,  destitute  of  opium,  are  sold  as  *'])aregoric  sub- 
stitute," &c.,  and  if  not  dangerous  in  themselves,  accustom  ignorant  persons 
to  give  and  take  large  doses,  which  when  repeated  with  genuine  paregoric 
cause  dangerous  and  even  fatal  efiects. 


358  DETECTION    OF   OPIUM. 

Detection  op  Morphine  and  Opium. — In  cases  of  suspected 
poisoning  the  detection  of  opium  is  based,  in  addition  to  the  recog- 
nition of  its  smell,  on  the  extraction  of  morphia  and  meconic  acid 
in  a  sufficiently  pure  form  to  allow  of  the  production  of  their 
characteristic  reactions.  The  following  is  the  usual  mode  of 
procedure : — 

Observe  if  any  smell  of  opium  is  apparent.  If  not,  it  may 
become  evident  on  gently  warming  some  •  of  the  contents  of  the 
stomach.  Test  a  small  quantity  of  the  strained  or  filtered  liquid 
with  ferric  cliloride,  and  note  if  any  red  coloration  (characteristic 
of  meconic  acid)  is  produced. 

Next  cut  up  the  stomach  and  any  solid  contents  into  small 
pieces,  and  reduce  the  whole  to  pulp  by  beating  in  a  mortar.  Mix 
the  product  with  the  liquid  contents  of  the  stomach,  and  treat  the 
whole  with  rectified  spirit  acidulated  with  acetic  acid,  in  sufficient 
quantity  .to  coagulate  the  albumin.^  Keep  the  mixture  warm  for 
some  time,  with  occasional  agitation.  Then  nlLer  or  strain  from 
the  solid  matter. 

The  filtrate  is  treated  with  basic  acetate  of  lead  as  long  as  a 
precipitate  is  produced,  when  the  liquid  is  boiled  and  allowed  to 
cool.  When  cold  it  is  again  filtered,  and  the  precipitate  washed 
with  cold  water.  The  precipitate  contains  the  meconic  acid  of  any 
opium  present.  It  should  be  washed  off  the  filter  with  water,  and 
completely  decomposed  by  passing  a  rapid  stream  of  sulphuretted 
hydrogen  gas.  The  liquid  is  next  filtered,  and  concentrated  to  a 
small  bulk  by  evaporation  at  as  low  a  temperature  as  possible.  It 
should  then  be  placed  in  a  porcelain  dish  and  tested  with  ferric 
chloride,  which  wiU  produce  a  purplish  red  coloration  if  meconic 
acid  be  present.  It  is  necessary  to  distinguish  carefully  between 
the  coloration  produced  by  meconic  acid  and  the  somewhat  similar 
reactions  given  by  thiocyanates  and  acetates.  This  may  be  effected 
with  certainty  as  described  on  page  338. 

A  very  useful  indication  of  the  amount  of  opium  present  may 
be  obtained  by  comparing  the  depth  of  tint  produced  by  ferric 
chloride  with  that  obtained  on  treating  a  known  quantity  of  opium 
in  a  similar  way. 

The  filtrate  from  the  lead  precipitate  will  contain  any  morphine 
which  may  have  been  present.  Separate  the  excess  of  lead  by 
passing  sulphuretted  hydrogen  for  some  time,  filter,  evaporate 
cautiously  nearly  to  dryness,  add  a  little  water  and  filter.  The 
filtrate  will   probably  have   a  bitter  taste  if  morphine  (or  other 

^  Meconic  acid  adheres  very  tenaciously  to  albuminous  matters,  and  hence 
the  precipitate  should  be  digested  with  strong  alcohol,  and  the  liquid  strained 
and  added  to  the  main  solution. 


DETECTION  OF  OPIUM.  359 

alkaloid)  be  present.  Transfer  the  solution  to  a  stoppered  separator, 
render  the  liquid  alkaline  with  ammonia  or  (preferably)  an  alkaline 
bicarbonate,  and  shake  with  hot  amy  lie  alcohol  without  delay,  as 
described  on  page  316.  The  amylic  alcohol  solution  is  then 
separated,  passed  through  a  dry  filter,  and  either  at  once  evaporated 
to  dryness,  and  the  residue  examined  by  the  colour-tests  described 
on  page  313  e^  seq.^  or  it  is  shaken  with  a  little  dilute  hydrochloric 
acid,  which  is  then  separated  and  examined  for  morphine.  An 
estimate  of  the  quantity  of  morphine  present  may  be  obtained 
from  the  intensity  of  colour  produced  by  the  iodic  acid  and 
ferricyanide  tests  (page  318). 

Instead  of  treating  the  alcoholic  extract  of  the  material  under 
examination  with  basic  acetate  of  lead,  as  described  in  the  fore- 
going process,  the  method  may  in  some  cases  be  shortened  and 
rendered  more  delicate  by  evaporating  off  the  alcohol  at  a  low 
temperature,  taking  up  the  residue  with  water,  filtering,  acidulating 
the  filtrate  with  dilute  sulphuric  or  hydrochloric  acid,  and  agitating 
with  ether.^  This  removes  meconic  acid,  though  not  perfectly, 
while  phosphates  and  other  interfering  matters  remain  in  the 
aqueous  liquid,  and  if  the  ethereal  layer  be  separated,  evaporated, 
and  the  residue  treated  with  hot  water,  a  solution  is  obtained, 
which  after  filtration  may  be  very  advantageously  used  for  the 
application  of  the  ferric  chloride  t^st.  If  preferred,  the  solution 
may  be  treated  with  lead  acetate,  and  the  meconic  acid  recovered 
from  the  filtered  and  washed  precipitate  by  decomposing  it  with 
sulphuretted  hydrogen. 

The  positive  detection  of  meconic  acid  affords  as  perfect  a  proof 
of  the  presence  of  opium  as  does  the  recognition  of  morphine 
itself ;  and  as  the  tests  for  and  methods  of  separating  meconic  acid 
from  foreign  matters  are  somewhat  more  satisfactory  than  those 
for  morphine,  and  the  acid  is  more  stable  than  the  alkaloid,  it 
occasionally  happens  that  the  acid  may  be  isolated  and  positively 
identified,  when  morphine  cannot  be  recognised  with  certainty 
(especially  where  ptomaines  may  be  present). ^  The  detection  of 
meconic  acid  of  course  indicates  the  pre-existence  of  actual  opium 
or  some  galenical  preparation  thereof,  and  not  morphine  or  one  of 
its  salts.  Hence  it  sometimes  enables  a  useful  distinction  to  be 
drawn  as  to  the  form  in  which  the  poison  was  taken. 

1  After  this  treatment  the  aqueous  liquid  may  be  rendered  alkaline  with 
sodium  bicarbonate,  and  agitated  with  hot  amylic  alcohol  for  the  extraction  of 
the  morphine. 

2  The  author  obtained  satisfactory  proof  of  the  presence  of  meconic  acid  in 
the  stomachs  of  two  children  exhumed  five  months  after  death,  whereas  no 
positive  conclusion  could  be  formed  as  to  the  presence  of  morphine. 


360  DETECTION   OF  OPIUM. 

It  not  unfrequently  happens,  even  in  cases  in  which  it  is  certain 
that  opium  was  the  cause  of  death,  that  no  trace  of  morphia  or 
meconic  acid  can  be  found  on  analysis  of  the  stomach  or  its  con- 
tents. In  other  cases  the  poison  has  been  detected  with  moderate 
facility  a  considerable  time  after  death.  The  cause  of  these 
discrepant  results  is  very  obscure,  but  they  are  probably  mainly 
dependent  on  the  opportunities  which  circumstances  have  given  for 
the  elimination  or  absorption  of  the  poison  before  death  has  ensued. 
Hence  the  failure  to  find  morphine  does  not  prove  that  its  adminis- 
tration was  not  the  cause  of  death.  Attempts  to  extract  morphine 
from  the  blood  and  tissues  have  usually  failed,  but  T.  G. 
W  0  r  m  1  e  y  has  succeeded  in  isolating  it  from  the  brain,  blood,  liver, 
and  urine  of  animals  poisoned  by  it  (Chem.  News,  Ixii.  79,  99). 

In  examining  urine  for  morphine,  a  considerable  quantity  of 
urea  is  liable  to  be  taken  up  by  the  amylic  alcohol.  If  the 
solution  in  this  menstruum  be  evaporated  and  treated  with  cold 
water,  a  notable  quantity  of  morphine  is  dissolved  together  with 
the  urea.  In  the  minute  quantity  present  it  may  be  extracted 
from  the  liquid  by  ether  (which  does  not  dissolve  urea),  or  prefer- 
ably by  a  mixture  of  ether  and  acetic  ether. 


STRYCHNOS  ALKALOIDS. 

The  various  species  of  Strychnos,  a  genus  of  plants  belonging  to 
the  order  Loganiacece,  contain  certain  alkaloids  remarkable  for 
their  intensely  poisonous  properties.  Of  these,  the  only  two 
which  have  been  thoroughly  investigated  are  strychnine 
and  brucine,  the  latter  base  being  probably  a  dimethoxy- 
strychnine. 

Strychnine  and  brucine  occur  in  the  seeds  of  the  Strychnos 
nvx  vomica,  in  combination  with  lactic  and  igasuric  acids.  A 
third  base,  igasurine,  has  been  supposed  to  exist  in  nux 
vomica ;  but  the  researches  ofW.  A.  Shenstone  {Jour.  Chem. 
Soc,  xxxix.  453)  have  proved  the  supposed  alkaloid  to  be  merely 
a  mixture  of  strychnine  and  brucine.  The  bark  of  Strychnos  nux 
vomica  is  also  very  poisonous,  and  is  sometimes  termed  "false 
angustura  bark."  The  extreme  bitterness  of  the  strychnos 
bark,  its  twisted  appearance,  the  impossibility  of  separating  it  into 
thin  layers,  and  the  blood-red  coloration  produced  on  applying 
nitric  acid  to  the  internal  coat,  are  characters  by  which  it  is  easy 
to  distinguish  it  from  true  angustura  bark. 

The  seeds  of  Strychnos  Ignatice,  commonly  called  "St 
Ignatius'  beans,"  also  contain  strychnine   and  brucine,  and 


STRYCHNINE.  361 

are  employed  for  the  manufacture  of  the  alkaloids,  of  which  they 
are  said  to  contain  from  IJ  to  2  per  cent,^ 

The  leaves  of  Stryclinos  nux  vomica  are  said  to  contain  brucine 
but  no  strychnine.^ 

The  decoction  of  the  root-bark  of  Strychnos  Tieute  or  "  deadly  upas 
tree  "  of  Java,  evaporated  to  an  extract,  is  the  chief  ingredient  of 
the  arrow-poison  upas-tieute.     It  contains  strychnine  and  brucine.^ 

The  deadly  effects  of  Ciirare  or  Indian  arrow-poison  have  been 
attributed  to  strychnine,  but  are  now  proved  to  be  due  to  a  distinct 
base,  c  u  r  a  r  i  n  e,  which  is  described  on  page  388. 

Strychnine.    Strychnia.    C21H22N2O2.2 

Strychnine  exists,  together  with  brucine,  in  the  seeds  and  bark 
of  Strychnos  nux  vomica,  in  the  seeds  of  S.  Ignatice,  called  "St 
Ignatius'  beans,"  and  in  certain  other  plants  of  the  same 
genus. ^  It  may  be  prepared  from  these  sources  by  a  method 
similar  to  that  used  for  their  assay  (page  385).^ 

Strychnine  occurs  as  a  white  powder,  or  in  crystalline  particles 
of  variable  appearance.     The  crystals  are  sometimes  minute  pearly 

*  Strychnine  appears  to  have  been  found  with  certainty  in  five  or  six  species 
of  Strychnos  only.     Several  of  the  genus  contain  neither  strychnine  nor  brucine. 

-  According  to  Claus  and  Glassner  {Ber.,  xiv.  773)  the  strychnine  of 
commerce  has  not  always  the  same  composition,  being  represented  in  some 
instances  by  the  formula  C22H22N2O2,  and  in  others  by  C21H22N3O2.  They 
believe  the  plant  produces  the  alkaloid  with  a  variable  proportion  of  carbon, 
a  supposition  which  has  also  been  entertained  by  Schiitzeuberger.  K  o  e  f  o  e  d, 
by  fractional  precipitation  of  commercial  strychnine  with  potassium  platinoso- 
chloride,  obtained  at  first  a  salt  containing  18  "8  per  cent,  of  Pt,  coiTesponding 
to  a  molecular  weight  of  347 '6  for  the  alkaloid,  while  the  precipitate  subse- 
quently thrown  down  contained  19'35  per  cent  of  platinum,  representing  a 
molecular  weight  of  333  2,  against  333*3  required  for  the  formula  CjiH-^oNoOj. 
Hence  commercial  styrchnine  probably  contains  homostrychnine 
0^1124X202,  in  addition  to  the  base  of  recognised  composition. 

*  Nux  vomica  seeds  or  St  Ignatius'  beans  are  boiled  with  dilute  sulphuric 
acid  till  soft,  then  crushed,  and  the  expressed  liquid  treated  with  slaked  lime  in 
excess.  The  precipitate  is  filtered  oflf  and  boiled  with  alcohol  of  0'85  specific 
gravity,  which  dissolves  the  alkaloids  and  deposits  the  strychnine  on  cooling, 
the  brucine  mostly  remaining  in  solution.  The  British  Pharmacopceia  directs 
that  the  powdered  seeds  shall  be  exhausted  with  dilute  alcohol,  the  spirit 
distilled  off",  and  the  solution  precipitated  with  acetate  of  lead.  From  the 
filtrate  the  alkaloids  are  precipitated  with  ammonia,  and  redissolved  in  boil- 
ing rectified  spirit,  the  greater  part  of  which  is  then  distilled  off.  The  residual 
liquid  on  cooling  deposits  the  strychnine,  which  is  washed  with  a  mixflire  of 
2  parts  of  rectified  spirit  and  1  of  water  till  the  washings  cease  to  become 
red  on  adding  nitric  acid,  indicating  freedom  from  brucine.  It  is  then  re- 
crystallised  from  boiling  alcohol. 


362  CHARACTERS   OF   STRYCHNINE. 

scales,  like  mica ;  sometimes  octahedra,  with  a  rhombic  base ;  but 
more  commonly  form  large,  four-sided  prisms.  The  crystals  vary 
much  according  to  the  solvent  from  which  they  are  deposited. 
For  their  production  on  a  microscopic  scale  it  is  best  to  let  the 
alkaloid  deposit  gradually  by  addition  of  an  alkali  to  the  solution 
of  one  of  its  salts ;  or  to  expose  the  solution  to  ammoniacal 
vapours  (see  page  364).  Well-formed  crystals  of  strychnine  are 
also  obtained  by  gradually  adding  v/ater  to  the  alcoholic  solution 
of  the  free  base. 

Crystallised  strychnine  has  an  approximate  specific  gravity  of 
1-13  (T.  P.  Blunt). 

Strychnine  has  no  smell  and  is  not  deliquescent.  On  being 
heated  it  melts  without  decomposition  at  265°-266°  C,  and 
sublimes  imperfectly.  Its  solutions  exert  a  Isevo-rotatory  action 
on  polarised  light,  have  a  marked  alkaline  reaction,  and  are 
extremely  bitter.^ 

Strychnine  is  an  exceedingly  violent  tetanic  poison  (page  372), 

Strychnine  is  very  sparingly  soluble  in  cold  water,  requiring 
about  8300  parts  for  its  solution,  but  it  dissolves  in  2500  parts  of 
boiling  water.  It  requires  207  parts  of  cold  absolute  alcohol  for 
solution,  and  about  400  of  whisky,  500  of  spirit  of  '941  sp.  gravity, 
and  2617  parts  of  "970  sp.  gravity.  The  limited  solubility  of 
strychnine  in  alcohol  is  utilised  for  its  separation  from  brucine, 
which  is  readily  soluble  in  the  same  liquid.  Strychnine  is  soluble 
in  8  to  10  parts  of  chloroform,  but  dissolves  very  sparingly  in 
ether,  requiring  1400  parts  of  the  anhydrous  menstruum,  or  about 
1050  of  ordinary  commercial  ether.  Doubtless  the  physical  condi- 
tion of  the  alkaloid  largely  affects  its  solubility.  Strychnine 
dissolves  with  facility  in  a  mixture  of  equal  measures  of  chloro- 
form and  ether — a  fact  often  utilised  for  its  extraction.  It  is 
soluble  also  in  140  parts  of  benzene,  and  is  deposited  on  spon- 
taneous evaporation  in  large  brilliant  octahedral  crystals.  In 
petroleum  ether  strychnine  is  nearly  insoluble,  requiring,  according 
to  Wormley,  about  12,500  parts  for  solution. 

Strychnine  is  not  removed  from  its  acidulated  solutions  by 
agitation  with  any  of  the  above  immiscible  solvents,  but,  on  the 
contrary,  may  be  completely  extracted  from  its  solutions  in  them 
by  shaking  the  liquid  with  dilute  sulphuric  acid. 

Strychnine  is  not  sensibly  soluble  in  solutions  of  the  fixed 
caustic  alkalies,  but  dissolves  somewhat  more  readily  in  ammonia. 
In  dilute  acids  it  is  readily  soluble. 

^  The  bitterness  of  strychnine  is  said  to  be  recognisable  in  a  solution  of 
^Vth  of  a  grain  per  gallon.  The  salts  of  stiychnine  are  much  less  bitter  than 
the  free  alkaloid. 


SALTS  OF  STRYCHNINE.  363 

Strychnine  dissolves  witHout  coloration  in  the  strong  mineral 
acids.  It  may  he  heated  to  100°  C.  with  strong  sulphuric  acid 
without  visible  change,  and  is  often  stated  to  be  unaltered  by  such 
treatment.  But  the  strychnine  cannot  be  wholly  recovered  from 
the  product,  and  C.  Stoehr  (5er.,  xviii.  3429)  has  shown  that  a 
sulphonic  acid  is  formed.^ 

Monobrom  strychnin  6,  CgiHgiBrNgOg,  is  obtained  on 
adding  bromine-water  in  theoretical  quantity  to  an  aqueous  solu- 
tion of  strychnine  hydrobromide  or  hydrochloride,  and  then  precipi- 
tating with  ammonia.  The  aqueous  solution  is  alkaline  and  very 
bitter  {Arch.  Fliarm.y  ccxxviii.  313). 

Salts  of  Strychnine. 

Strychnine  is  a  strong  base,  and  forms  salts  which  are  usually 
crystallisable  and  soluble  in  water,  yielding  very  bitter,  exceedingly 
poisonous  solutions.  The  salts  of  strychnine  are  mostly  soluble 
in  alcohol,  but  are  insoluble  in  ether,  chloroform,  benzene,  petroleum 
spirit,  or  amylic  alcohol. 

Strychnine  may  be  titrated  with  accuracy  by  a  standard  mineral 
acid,  using  litmus  or  methyl-orange  as  an  indicator.  One  c.c.  of 
decinormal  acid  corresponds  to  0"0334  gramme  of  strychnine. 
Strychnine  has  no  effect  on  phenolphthalein,  and  hence  its  salts 
react  with  this  indicator  as  if  the  acids  were  uncombined. 

The  cliromate,  ferrocyanide,  mercurochloride,  pliosphotungstate; 
and  phosphomolybdate  are  among  the  most  insoluble  salts  of  strych- 
nine. All  these  forms  are  occasionally  used  for  the  isolation  or 
estimation  of  the  alkaloid.  The  high  insolubility  of  the  ferro- 
cyanide  serves  to  separate  the  alkaloid  from  brucine. 

The  sparing  solubility  of  the  hydriodide  of  strychnine  is  important, 
as  the  salt  is  liable  to  be  thrown  down  in  the  form  of  crystalline 
needles  from  mixtures  in  which  strychnine  hydrochloride  and  a 
metallic  iodide  are  dispensed  together.  The  hydrobromide  is 
stated  to  be  similarly  liable  to  separate  out. 

None  of  the  salts  of  strychnine  find  any  place  in  the  British 
Pharmacopoeia.  The  sulphate  is  official  in  the  United  States,  and 
the  nitrate  in  Germany.  The  following  table  indicates  the  lead- 
ing characters  of  the  principal  salts  of  strychnine. 

*  Strychnine-monosulphonio  Acid,  CaiHoiNaOg-SOgH,  is  produced  in 
nearly  theoretical  amount  when  strychnine  is  heated  to  100°  with  the 
requisite  quantity  of  concentrated  sulphuric  acid.  The  free  acid  is  colourless, 
and  very  little  soluble  in  water  or  alcohol.  The  ammonium  salt  is 
very  soluble  in  water,  but  precipitated  by  alcohol ;  and  the  potassium, 
sodium,  barium,  calcium,  lead,  and  copper  salts  form  very  insoluble 
precipitates.  With  fuming  sulphuric  acid  at  150°  a  soluble  disulphonic  CLcid 
is  formed. 


364 


REACTIONS  OF  STRYCHNINE. 


Salt 

Foimula. 

Appearance. 

Pi-oportion  of 
Strychnine. 

Solubility. 

Cold  Water. 

Boiling  Water. 

Hydrochloride, 
Hydrobromide, 
Hydriodide,     . 

Nitrate,    .       . 
Sulphate, 

Acid  sulphate, 
Acetate,  . 

BHCl 
BHBr 
BHI 

BHNO3 

B2H28O4+ 

6  aqua 

(or  5  aqua) 

BH2SO4+ 

2  aqua 

Silky  needles. 

Prismatic 
needles. 

Quadrangular 
needles,    or 
white  scales. 

Silky  needles. 

Transparent 
quadratic 
octahedra. 

Long,  thin 
needles. 

Crystallises 

with  difficulty. 

84    per  cent. 
80         „ 
72-3      „ 

84 

76-4      „ 

71-4      „ 

1  part  in  50 

„       32 

Sparingly. 

1  part  in  90 
„       42 

1  part  in  96 

1  part  ui  3 

M           2 

Analytical  Reactions  of  Strychnine. 

1.  On  adding  to  a  not  too  dilute  solution  of  a  soluble  salt  of 
strychnine  a  fixed  caustic  alkali,  alkaline  carbonate,  ammonia,  or 
lime-water,  strychnine  is  thrown  down  as  a  white  precipitate 
insoluble  in  excess  of  the  precipitant.  The  precipitate  rapidly 
becomes  crystalline.  The  crystals  have  a  characteristic  microscopic 
appearance,  being  usually  long,  rectangular,  well-defined  prisms. 
They  are  well  developed  if  a  drop  of  a  dilute  solution  of  a  strych- 
nine salt  {e.g.,  the  acetate  or  sulphate)  be  placed  on  a  slip  of  glass, 
and  covered  with  a  small  beaker  rinsed  with  strong  ammonia. 
After  half  an  hour  the  beaker  may  be  removed,  the  drop  of  liquid 
covered  with  a  circle  of  thin  glass,  and  examined  under  the  micro- 
scope. If  the  solution  contain  extraneous  matter,  it  may  be  found 
difficult  or  impossible  to  obtain  crystals  from  it. 

2.  If  strychnine  be  liberated  from  the  solution  of  one  of  its 
salts  by  one  of  the  reagents  mentioned  above,  and  the  liquid  (with 
the  suspended  precipitate)  be  at  once  shaken  with  an  equal  measure 
of  chloroform,  the  alkaloid  is  readily  dissolved  by  the  latter  liquid, 
and  may  be  obtained  in  a  solid  state  by  separating  the  chloroform 
and  evaporating  it  to  dryness  at  a  steam  heat.  The  agitation  of  the 
aqueous  liquid  with  chloroform  should  be  repeated  if  quantitative 
results  are  desired.  From  aqueous  liquids  containing  little  solid 
matter,  chloroform  separates  tolerably  readily,  but  if,  as  often 
happens  in  practice,  there  be  much  extractive  matter  present,  the 
complete  separation  of  the  chloroform  requires  many  hours  or  even 
days.  This  inconvenience  may  be  wholly  avoided  by  substituting 
for  pure  chloroform  a  mixture  of  equal  volumes  of  ether  and 
chloroform.  This  has  a  density  of  1*11,  and  separates  with  facility 
from  aqueous  liquids  (compare  pages  156  and  374).     Experiments 


PKECIPITANTS  OF  STKYCHNINE.  365 

by  the  author  have  shown  that  the  solubility  of  strychnine  in  a 
mixture  of  equal  measures  of  chloroform  and  ether  is  amply  sufficient 
to  ensure  its  separation  from  the  aqueous  liquid  (Analyst,  vi.  141). 

3.  A  very  useful  precipitant  for  strychnine  in  complex  organic 
liquids  is  a  nitric  acid  solution  of  sodium  phosphomolybdate 
(Sonnenschein's  reagent,  page  136).  On  adding  this  to 
a  neutral  or  slightly  acid  solution  of  the  alkaloid,  the  strychnine  is 
thrown  down  as  a  yellowish  white  amorphous  precipitate.  The 
separation  is  complete  even  in  very  dilute  liquids.  Many  alkaloids 
besides  strychnine  give  similar  precipitates,  and  hence  the  reagent 
is  merely  of  service  for  concentrating  the  strychnine  and  purifying 
it  from  extraneous  matters.  The  precipitate  should  be  filtered  off, 
washed  with  water  containing  the  reagent,  and  the  strychnine 
separated  by  suspending  the  precipitate  in  water,  adding  ammonia, 
and  agitating  with  ether-chloroform,  as  in  test  2.  The  precipitate 
can,  however,  be  directly  examined  by  the  colour-reactions  described 
on  page  368. 

4.  Scheibler's  reagent  (page  136)  precipitates  strych- 
nine from  extremely  dilute  solution,  and  may  be  substituted  (with 
advantage)  for  the  phosphomolybdic  reagent. 

5.  Strychnine  may  also  be  separated  from  its  tolerably  concen- 
trated neutral  solutions  by  precipitation  with  chromate  of  potas- 
sium. The  test  is  best  applied  to  a  chloroform-residue  obtained 
as  described  in  2.  This  should  be  dissolved  in  dilute  acetic  acid, 
the  liquid  filtered,  if  necessary,  and  evaporated  to  dryness  at  100°. 
The  resultant  acetate  of  strychnine  is  dissolved  in  a  little  cold 
water,  and  neutral  chromate  of  potassium  is  added  to  the  solution. 
Strychnine  chromate,  (C2iH22N202)2,H2Cr04,  is  thrown 
down  as  a  reddish  or  yellowish  brown  precipitate,  soluble  in  boiling 
water  (1  in  171)  and  re-deposited  on  cooling  in  orange-  or  lemon- 
yellow  needles  and  plates.  The  precipitate  is  very  slightly  soluble 
in  cold  water  (1  in  470),  a  fact  which  enables  strychnine  to 
be  separated  from  brucine,  the  chromate  of  which  is  more  soluble. 
Potassium  bichromate  throws  down  from  solutions  of  strychnine, 
not  too  dilute,  an  anhydrochromateof  the  formula  B2H2Cr207 
as  a  crystalline  precipitate,  in  which  octahedra  and  bush-like 
groups  are  the  most  prominent  microscopic  forms.  The  precipitate 
is  not  soluble  in  excess  of  the  reagent  or  in  very  dilute  acids,  and 
its  formation  is  much  facilitated  by  stirring.  It  dissolves  in  1800 
parts  of  cold  and  about  240  parts  of  boiling  water,  and  is  rapidly 
affected  by  exposure  to  light.  The  chromates  of  strychnine  give 
the  characteristic  violet  oxidation-product  directly  on  treatment 
with  strong  sulphuric  acid  as  described  in  paragraph  8  ;  or  the 
alkaloid  may  be  obtained  in  a  free  state  by  suspending  the  pre- 


366  REACTIONS   OF  STRYCHNINE. 

cipitate  in  water,  adding  ammonia,  and  agitating  with  ether-chloro- 
form, as  in  2. 

6.  With  iodised  potassium  iodide  strychnine  gives  a  reddish- 
brown  precipitate,  even  in  extremely  dilute  solutions  (1  :  100,000). 
Mayer's  reagent  also  precipitates  strychnine  from  very  dilute  solu- 
tions (1  :  160,000),  and  is  recommended  by  G.  F.  Schacht  for 
its  determination. 

7.  Strychnine  forms  a  combination  with  iodine  analogous  to, 
and  having  similar  optical  properties  with,  herepathite.  The 
following  is  the  best  method  of  utilising  the  reaction  for  the 
detection  of  strychnine.  On  a  microscope-slide  place  a  very  small 
drop  of  an  alcoholic  solution  of  iodine,  and  allow  it  to  evaporate. 
Directly  it  is  dry  add  a  drop  of  a  solution  of  strychnine,  made  by 
dissolving  the  alkaloid  in  dilute  acetic  acid  and  adding  a  drop  of 
sulphuric  acid.  Add  also  a  drop  of  rectified  spirit,  and  allow  the 
mixture  to  evaporate  spontaneously.  On  examining  the  residue 
under  the  microscope  with  a  Nicol's  prism  and  selenite,  but  using 
no  analyser,  characteristic  crystalline  structures  will  be  observed. 
These  may  take  the  form  of  small  circular  tufts  of  very  fine  black 
needles ;  of  minute  dots  of  a  more  or  less  triangular  form,  exhibit- 
ing yellow,  pink,  and  green  tints ;  large  triangular  crystals  of  a 
yellow  or  green  colour,  composed  of  three  parts  radiating  from  a 
centre ;  numerous  solid  macled  prisms,  occasionally  showing  com- 
plementary tints ;  or  solid  rosettes  of  four,  five,  and  six  sided 
prisms.  In  all  cases  it  is  desirable  to  compare  the  results  with 
those  obtained  from  a  minute  quantity  of  strychnine  treated  in 
precisely  the  same  manner.  The  mode  of  operation  may  be  varied 
considerably,  provided  that  the  essential  conditions  of  simultaneous 
presence  of  alcohol,  sulphuric  acid,  acetic  acid,  free  iodine,  and  a 
trace  of  strychnine  be  duly  observed.  The  test  is  said  to  be  sensi- 
tive to  1-2500  of  a  grain  of  strychnine. 

8.  When  potassium  ferrocyanide  is  added  to  the  solution  of  a 
salt  of  strychnine,  the  ferrocyanide  of  the  base,  l^^^QCyQ-\-iHfi, 
is  precipitated  as  a  white  crystalline  powder  with  a  shade  of 
yellow,  only  very  sparingly  soluble  in  cold  water.  The  observa- 
tion, which  is  due  to  Beckurts,  has  been  utilised  by  D  u n- 
stan  and  Short  {Tear-Book  Pharm.,  1883,  page  469)  for  the 
determination  of  strychnine  and  its  separation  from  brucine,  the 
ferrocyanide  of  which  is  readily  soluble.  A  quantity,  not  exceed- 
ing 0*2  gramme,  of  the  mixed  alkaloids  is  dissolved  in  about 
10  CO.  of  water  containing  5  per  cent,  by  measure  of  strong  sul- 
phuric acid,  the  solution  diluted  with  water  to  about  175  c.c,  and 
then  made  up  to  200  c.c,  with  a  5  per  cent,  aqueous  solution  of 
potassium  ferrocyanide.     The  liquid  is  stirred  occasionally  during 


DETERMINATION   OF  STRYCHNINE.  367 

six  hours,  and  is  then  filtered  off  and  washed  with  watei  acidulated 
with  ^  of  sulphuric  acid,  till  the  washings  are  free  from  bitter- 
ness. As  the  precipitate  is  liable  to  alteration  on  drying,^  it  should 
be  washed  off  the  filter  with  strong  ammonia  and  extracted  by- 
agitation  with  chloroform.  After  separating  the  chloroform  solu- 
tion and  washing  it  with  water,  the  strychnine  may  be  titrated  by 
standard  acid  and  methyl-orange,  or  the  chloroform  may  be  evapo- 
rated to  dryness  and  the  residual  alkaloid  weighed.  Some  alcohol 
should  be  added  towards  the  end  of  the  evaporation  to  prevent  the 
violent  decrepitation  which  otherwise  ensues.^  From  the  filtrate 
from  the  ferrocyanide  precipitate  the  brucine  may  be  precipitated 
by  ammonia  and  extracted  by  chloroform.  S  c  h  w  e  i  s  s  i  n  g  e  r 
{Archiv  des  Pharm.,  [3],  xii.  579,  609)  states  that  he  had  not 
found  the  ferrocyanide  method  to  effect  a  perfect  separation  of 
strychnine  and  brucine.  He  found  strychnine  ferrocyanide  to  be 
perfectly  insoluble  in  water  acidulated  with  suljihuric  acid,  but  the 
brucine  salt  was  not  completely  soluble,  and  was  precipitated  more 
or  less  perfectly  after  a  time.  Hence  the  strychnine  was  always 
estimated  too  high  and  the  brucine  too  low,  the  error  largely  depend- 
ing on  the  time  allowed  and  the  concentration  of  the  liquid. 

When  the  precipitation  of  the  strychnine  as  ferrocyanide  is 
effected  in  a  liquid  strongly  acid  with  hydrochloric  acid,  the  salt 
thrown  down  is  insoluble  in  cold  water  and  alcohol,  has  a  bluish 
shade,  and  is  an  acid  ferrocyanide  containing  B,H4FeCyg. 
No  similar  precipitate  is  obtained  with  brucine  except  in  highly 
concentrated  solutions,  or  after  long  standing.  Hoist  and 
Beckurts  {Arch.  Pliann.,  [3],  xxv.  313)  have  based  on  this 
fact  the  following  volumetric  method  of  determining  strychnine. 
A  1  per  cent,  solution  of  the  alkaloids  is  strongly  acidulated  with 
hydrochloric  acid,  and  a  standard  solution  of  potassium  ferro- 
cyanide solution  added  until  a  filtered  portion  of  the  liquid  gives 
a  blue  stain  with  paper  moistened  with  ferric  chloride.  224  parts 
of  ferrocyanide  represent  334  of  strychnine.  The  following 
results  were  obtained  : — 


strychnine. 

Brucine. 

taken.                   found. 

taken.                   found. 

No.  1,    . 

.     0-145  grm.         0-148  gvm. 

0  036  grm. 

No.  2,   . 

.     0-100     „            0-1017  „ 

0-050     ,,         0-04915  grm. 

^  According  to  Beckurts,  upou  exposure  to  air  strychnine  ferrocyanide 
turns  yellow,  and  is  eventually  completely  decomposed  with  formation  of 
strychnine  ferrocyanide  and  a  new  base  which  can  be  extracted  with  alcohol, 
called  oxystrychnine,  C21H02N2O3. 

2  Dunstan  and  Short  state  that  this  behaviour  is  characteristic  of  pure 
strychnine,  a  minute  admixture  of  brucine  preventing  it  and  causing  thie 
alkaloid  to  have  a  fused  appearance. 


368  OXIDATION -TEST   FOR   STRYCHNINE. 

9.  On  treating  a  cold  solution  of  strychnine  in  concentrated 
sulphuric  acid  with  an  oxidising  agent  of  almost  any  kind,  a 
rich  purple-blue  coloration  is  developed.  This  changes  more  or 
less  rapidly  through  purple  and  crimson  to  a  bright  cherry- red 
tint,  which  is  somewhat  persistent.  The  rapidity  of  the  change 
of  colour  is  largely  dependent  on  the  nature  and  quantity  of  the 
oxidising  agent  employed.  Various  substances  have  been  re- 
commended for  the  purpose.  The  following  are  the  most 
notable : — 

(a)  Potassium  bichromate.  This  is  a  favourite  oxidising  agent 
with  many  operators,  but  in  the  experience  of  the  author  is  one 
of  the  least  reliable  reagents  for  the  purpose,  as  the  change  of 
colour  is  very  rapid  and  the  green  chromium  compound  resulting 
from  the  reaction  tends  to  mark  the  coloration  due  to  the 
strychnine. 

A  useful  way  of  employing  bichromate  is  to  precipitate  the 
strychnine  by  means  of  it  (as  in  5),  and  apply  sulphuric  acid  to 
the  precipitate.  This  plan  has  the  great  advantage  of  separating 
brucine,  the  presence  of  which  is  objectionable. 

(b)  Potassium  permanganate,  originally  recommended  by  Guy, 
gives  the  reaction  with  great  distinctness,  but  the  rotation  of  tints 
is  very  rapid,  and  the  reagent  itself  is  apt  to  give  a  crimson 
colour  with  sulphuric  acid. 

(c)  Potassium  ferricyanide,  a  reagent  proposed  by  E.  Davy, 
gives  exceedingly  good  results.  The  change  from  blue  to  crimson 
and  red  is  very  rapid. 

{d)  Lead  dioxide  (PbOg).  This  oxidising  agent,  suggested  by 
M  a  r  c  h  a  n  d,  acts  remarkably  well,  but  the  puce  colour  natural 
to  it  is  apt  to  distract  the  attention  from  the  reaction  to  be 
looked  for. 

(e)  Manganese  dioxide  (MnOg).  This  reagent,  originally  re- 
commended by  Mack,  employed  in  moderate  quantity  and  in 
the  finally  powdered  state,  is  the  one  to  which  the  author  gives 
preference.  The  play  of  colours  is  remarkably  well-developed, 
and  the  change  of  tint  very  gradual. 

P.  R  Mandelin  recommends  a  solution  of  1  gramme  of 
ammonium  vanadate  in  100  c.c.  of  sulphuric  acid  as  a  reagent 
which  will  keep  unchanged,  and  which  gives  the  colour-reaction 
with  great  distinctness. 

(/)  Cerosoceric  oxide  (CegO^)  has  been  highly  recommended  as 
the  oxidising  agent  by  S.  D.  Hinsdale.  It  has  the  advantage 
of  being  light  in  colour,  and  giving  a  colourless  reduction- 
product. 

The  oxidation-test  for  strychnine  is  usually  performed  in  practice 


DETECTION   OF   STRYCHNINE.  369 

on  the  residues  left  by  evaporating  to  dryness  the  ether-chloroform 
with  which  an  alkaline  solution  of  the  alkaloid  has  been  agitated. 
The  test  may,  however,  be  directly  applied  to  the  chromate  or 
phosphomolybdate  of  strychnine  (see  reactions  4  and  5).  The 
following  mode  of  operating  is  best  calculated  to  ensure  delicacy 
and  accuracy : — 

The  solution  of  the  strychnine  in  ether-chloroform  should  be 
evaporated  in  a  porcelain  dish  or  crucible.  If  the  quantity  of 
strychnine  to  be  sought  for  is  likely  to  be  very  small,  the  dish 
should  be  immersed  in  hot  water,  and  the  solution  of  the  alkaloid 
allowed  to  fall  slowly  into  it  from  a  burette  or  pipette,  so  that 
each  drop  may  almost  completely  evaporate  before  another  arrives. 
In  this  manner  the  strychnine-residue  may  readily  be  confined  to 
a  very  small  area,  and  the  after-reactions  thus  rendered  propor- 
tionately delicate.  When  quite  dry  and  cold  the  residue  should 
be  treated  with  two  or  three  drops  of  pure  concentrated  sulphuric 
acid,  which  should  be  thoroughly  incorporated  with  it  by  means 
of  a  glass  rod.  The  mixture  should  then  be  allowed  to  stand 
for  five  minutes  in  order  to  note  if  any  colour  is  produced. 
Salicin  and  certain  other  bodies  will  cause  a  red  coloration,  while 
some  may  be  more  or  less  charred.  If  any  marked  coloration  is 
produced,  the  dish  should  be  gently  heated  (not  to  the  boiling- 
point  of  water)  for  half  an  hour,  the  contents  diluted  with  water, 
filtered,  made  alkaline  with  ammonia,  agitated  with  a  mixture  of 
ether  and  chloroform  (as  in  test  2),  and  the  strychnine  recovered 
by  evaporating  the  solvent.  The  residue  is  then  again  treated 
with  a  drop  or  two  of  sulphuric  acid. 

The  oxidising  agent,  which  should  be,  by  preference,  manganese 
or  lead  dioxide,  is  then  added  to  the  sulphuric  acid  by  dipping  a 
glass  rod  moistened  with  the  latter  into  the  powdered  solid.  A 
moderate  quantity  only  should  be  used,  so  as  not  to  obscure  the 
reaction  by  excess  of  blackness.  On  stirring  the  drop  of  strych- 
nine solution  with  the  rod  dipped  in  the  oxide  the  blue  coloration 
will  become  developed.  In  a  minute  or  so  it  will  be  distinctly 
purple,  passing  in  a  few  minutes  to  crimson,  and  ultimately  to  a 
cherry-red,  the  last  tint  being  very  persistent.  The  test  is  exceed- 
ingly satisfactory,  delicate,  and  characteristic,  but  the  order  of 
colours  is  as  important  as  their  shades.  The  reaction  is  said  to  be 
capable  of  detecting  ^-qo^o^^  ^^  ^  grain  of  strychnine.^ 

There  are  but  very  few  substances  which  at  all  simulate  the 
reaction  of  strychnine  when  treated  with  sulphuric  acid  and  an 

^  The  oxidation-reaction  has  been  applied*  by  Da  vies  and  Schmidt  to 
the  approximate  determination  of  the  strychnine  in  Easton's  Syrup 
{Year-Book  Pharvi.,  1883,  page  571). 

VOL.  III.  PART  II.  2  A 


370  DETECTION  OF  STRYCHNINE. 

oxidising  agent,  and  few  indeed  of  these  that  are  dissolved  together 
with  strychnine  on  agitating  the  alkaline  solution  with  ether- 
chloroform.  Salicin,  santonin,  pipeline,  solanine, 
certain  opium  bases,  cod-liver  oil,  and  certain  resins 
give  colours  with  sulphuric  acid  alone,  but  they  are  extracted  from 
acid  solutions  by  ether  and  chloroform,  and  certain  of  them  may 
also  be  got  rid  of  by  gently  heating  the  liquid  as  already  described. 
Aniline  gives  no  colour  with  sulphuric  acid  alone,  but  coloured 
products  are  formed  on  treating  the  solution  with  an  oxidising 
agent.  These  cannot  be  mistaken  for  the  oxidation-products  from 
strychnine,  for  the  order  of  tints  is  entirely  different,  commencing, 
in  the  case  of  aniline,  with  a  green,  changing  to  a  very  persistent 
blue,  and  ultimately  becoming  black.  Colocynth  resin  gives 
a  very  similar  reaction  to  strychnine,  but  is  readily  extracted  by 
agitating  the  acidulated  solution  with  benzene  or  ether. 

It  is  always  desirable  to  purify  the  strychnine  by  extracting  it 
from  an  alkaline  liquid  by  agitation  with  ether-chloroform  (see  page 
364),  but  the  oxidation-reaction  is  readily  obtained  even  in  presence 
of  considerable  quantities  of  certain  foreign  matters.  Thus  oat- 
meal, tartar-emetic,  and  dextrin  do  not  materially  interfere  with 
reaction  when  the  quantity  of  strychnine  is  considerable.  Some 
■extractive  matters,  sugar,  and  nitrates  wholly  prevent  the  applica- 
tion of  the  colour-test,  and  hence  the  absence  of  strychnine  must 
never  be  assumed  till  the  test  has  been  applied  to  an  ether- 
chloroform  residue. 

Quinine,  cinchonine,  and  veratrine  may  be  found 
with  strychnine  in  the  ether-chloroform  residue,  but  do  not  interfere 
with  the  application  of  the  test.  Morphine  in  small  proportion 
does  not  interfere,  and  the  presence  of  any  larger  quantity  than 
traces  is  excluded  by  its  limited  solubility  in  the  ether-chloroform. 

In  small  proportions  brucine  exercises  no  injurious  influence 
on  the  oxidation-test  for  strychnine,  but  when  much  is  present  it 
interferes  in  a  marked  manner.  Hence  it  is  safest  to  separate  the 
strychnine  first  of  all  as  chromate  or  ferrocyanide,  as  described  in 
reactions  5  and  7,  or  a  strong  solution  of  a  salt  of  the  alkaloid  can 
be  treated  with  a  very  decided  excess  of  ammonia,  when  the 
strychnine  will  be  precipitated  and  the  brucine  will  remain  in 
solution.  If  a  mixture  of  brucine  and  strychnine  be  treated 
with  chlorine-water,  the  former  base  dissolves  as  dichloro- 
brucine,  and  the  residue  then  gives  the  colour-reaction  perfectly 
(Beckhurts).  Brucine  can  be  sought  for  in  the  filtrate,  as 
described  on  page  383.  In  toxicological  investigations  its  presence 
together  with  strychnine  points  to  an  administration  of  one  of  the 
natural  sources  of  the  alkaloids,  rather  than  to  the  use  of  a  purified 


REACTIONS   OF   STRYCHNINE.  371 

salt  of  strychnine.  Commercial  strychnine  and  its  salts  often  con- 
tain traces  of  brucine,  but  not  sufficient  to  interfere  at  all  with 
the  application  of  the  oxidation-test. 

Curarine,  the  active  principle  of  the  Indian  arrow-poison, 
gives  a  series  of  coloured  oxidation-products  exactly  like  those  of 
strychnine,  but  not  being  sensibly  soluble  in  chloroform  it  is  not 
liable  to  be  found  in  the  chloroform-residue  (see  page  389). 

A  ptomaine  has  been  described  by  C.  Amthor  (Chem. 
Zeit,  xi.  228),  which  gives  a  blue  colour  with  the  oxidation-test 
less  persistent  and  pure  than  that  produced  by  strychnine.  It  is 
less  bitter  and  less  poisonous  to  frogs  than  strychnine,  is  dissolved 
readily  by  amy  lie  alcohol  but  only  slightly  by  ether  from  alkaline  so- 
lutions, and  gives  an  amorphous  chromate,  picrate,  ferrocyanide,  and 
f erricyanide.     The  formation  of  any  such  ptomaine  must  be  very  rare. 

Many  of  the  above  sources  of  fallacy  or  confusion  may  be  wholly 
avoided  by  performing  the  oxidation-test  in  a  manner  suggested  by 
H.  Letheby,  which  consists  of  employing  electrolytic  oxygen  instead 
of  either  of  the  oxidising  agents  mentioned  on  page  368.  The 
solution  of  the  ether-chloroform  residue  in  a  drop  or  two  of  strong 
sulphuric  acid  is  placed  in  a  cup-shaped  depression  in  a  piece  of 
platinum  foil.  The  foil  is  connected  with  the  platinum  plate  of  a 
single  Grove's  cell,  and  a  platinum  wire  connected  with  the  zinc 
plate  of  the  battery.  Immediately  that  the  end  of  this  platinum 
wire  is  dipped  into  the  drop  of  acid,  the  violet  colour  of  the  oxida- 
tion-product will  flash  out,  and  on  removing  the  wire  from  the 
liquid  the  tint  will  remain.^ 

8.  A  colour-reaction  of  strychnine  with  chloride  of  zinc  is 
described  on  page  145. 

9.  If  solid  strychnine  be  dissolved  in  a  drop  of  dilute  nitric 
acid,  the  liquid  gently  heated,  and  a  minute  particle  of  potassium 
chlorate  then  added  to  the  warm  liquid,  an  intense  scarlet  coloration 
is  produced.  This  is  changed  to  brown  on  adding  ammonia,  and  on 
evaporation  to  dryness  a  dark  green  residue  is  left,  soluble  in  water 
with  green  colour  changed  to  orange-brown  by  caustic  potash,  and 
becoming  green  again  on  adding  nitric  acid.  C.  L.  B 1  o  x  a  m,  the 
observer  of  the  foregoing  series  of  colour-changes  {Che7n.  News, 
Iv.  155)  did  not  obtain  any  corresponding  reaction  with  the  other 
alkaloids  he  tried. 

10.  A  reagent  prepared  by  adding  sufficient  strong  hydrochloric 
acid  to  a  weak  solution  of  potassium  chlorate  to  render  it  bright 

^  The  reaction  may  be  rendered  still  moB^  delicate  by  placing  the  drop  of 
liquid  at  the  bottom  of  a  porcelain  crucible,  and  momentarily  immersing  in  the 
liquid  two  platinum  wires  connected  respectively  with  the  zinc  and  platinum 
plates  of  the  battery. 


372  PHYSIOLOGICAL  TEST   FOR   STRYCHNINE. 

yellow,  and  then  sufficient  water  to  make  it  a  very  pale  yellow, 
gives  with  a  solution  of  strychnine  in  hydrochloric  acid  a  fine  red 
colour,  destroyed  by  excess  and  restored  by  boiling.  Brucine  gives 
a  violet  coloration  (C.  L.  B 1  o  x  a  m,  loc.  cit.). 

11.  An  exceedingly  delicate  test  for  strychnine  is  the  physio- 
logical one  of  Marshall  Hall.  A  freshly-caught  frog,  the 
smaller  the  better,  is  the  best  subject  for  the  experiment.  The 
skin  of  the  back  should  be  raised  with  a  pair  of  forceps,  and  a 
small  slit  made  with  a  pair  of  scissors.  Into  the  opening,  the 
suspected  liquid,  as  concentrated  as  possible,  should  be  injected  by 
means  of  a  small  pipette.  The  first  symptom  observed  will  be  a 
difficulty  in  breathing,  which  gradually  increases  till  the  animal 
appears  to  gasp  for  breath.  A  slight  tremor  will  be  observed 
extending  over  the  whole  body,  but  specially  noticeable  in  the 
hind  legs.  The  frog  sometimes  remains  perfectly  quiet,  but  in 
other  cases  takes  energetic  and  convulsive  leaps.  It  should  be 
placed  under  a  beaker  or  bell-glass  for  easier  observation.  The 
characteristic  tetanic  convulsions  next  make  their  appearance.  They 
are  intermittent,  the  pupils  being  dilated  during  the  spasms  and 
contracted  in  the  intervals.  The  convulsions  may  be  induced  by 
touching  the  frog,  clapping  the  hands,  or  knocking  on  the  table. 

The  physiological  test  is  much  reduced  in  practical  value  by  the 
difficulty  in  obtaining  young  animals  for  experiment.  On  the 
whole  it  is  decidedly  less  certain  and  characteristic  than  the  chemical 
reactions,  and  in  no  case  should  be  implicitly  relied  on  unless 
confirmed  by  the  results  of  the  oxidation-test. 

Toxicology  op  Strychnine. 

Owing  to  the  violently  poisonous  character  of  strychnine,  and 
the  ease  with  which  its  preparations  (under  the  disguise  of 
"  vermin-killers,"  &c.)  may  be  obtained  by  the  public,  cases  of 
death  from  its  effects  are  very  numerous.^ 

The  symptoms  of  poisoning  by  strychnine  usually  commence  with 
a  bitter  taste,  followed  by  a  feeling  of  sufi'ocation.  The  charac- 
teristic tetanic  convulsions,  often  accompanied  by  opisthotonos, 
then  come  on,  gradually  becoming  more  frequent.^  Vomiting  is 
not  common.     Lockjaw  is  a  constant  symptom.     Consciousness,  as 

^  In  the  author's  own  experience  of  the  examination  of  poisoned  animals,  ex- 
tending over  many  years  and  to  a  great  number  of  cases,  strychnine  has  been 
found  more  frequently  than  all  other  kinds  of  poison  taken  together.  He  has 
met  with  it  in  several  cases  of  murder  of  human  beings,  the  criminals  subse- 
quently undergoing  capital  punishment,  and  in  numerous  cases  of  suicide  and 
death  by  misadventure,  including  careless  dispensing  by  a  qualified  medical  man. 

2  Methyl-strychnine  produces  a  paralysing  effect  more  allied  to  that  due  to 
curare  than  to  the  tetanising  effect  of  strychnine. 


POISONING  BY  STRYCHNINE.  373 

a  rule,  is  retained  till  the  last,  accompanied  by  a  lively  terror  of  the 
rapidly-recurring  and  agonising  fits.  Death  usually  ensues  within 
a  few  hours,  but  in  rare  cases  life  has  been  prolonged  for  several 
days.     The  general  time  is  from  thirty  to  ninety  minutes.^ 

From  ^2  ^  iV  ^^  ^  grain  is  the  usual  medicinal  dose  of  strych- 
nine, but  it  may  be  increased  in  the  case  of  a  person  accustomed 
to  it.  One-sixth  of  a  grain  is  usually  distinctly  dangerous.  One 
grain  may  be  regarded  as  the  average  fatal  dose  for  an  adult,  and 
death  has  been  known  to  occur  from  J  grain.  Much  larger  doses 
have  been  recovered  from.^ 

Hypodermic  injections  of  strychnine  have  been  very  successfully 
employed  as  an  antidote  in  cases  of  snake  bite.^ 

The  post-mortem  appearances  of  poisoning  by  strychnine  are  not 
very  striking  or  characteristic.  Rigidity  of  the  muscles  is  usually 
prolonged,  but  if  death  occur  in  one  of  the  intervals  between  the 
fits,  no  rigidity  will  be  observed.  The  heart  is  usually,  but  not 
always,  full  of  blood,  especially  on  the  right  side.  The  stomach 
usually  appears  normal,  but  sometimes  intensely  congested.'*     The 

^  In  a  case  within  the  author's  experience,  in  which  medicine  containing 
a  poisonous  dose  of  strychnine  was  taken,  the  victim,  a  young  woman,  imme- 
diately cried  out  that  she  was  poisoned,  and  died  in  twelve  minutes.  Analysis 
of  the  remainder  of  the  medicine  showed  the  presence  of  rather  more  than  one 
grain  of  strychnine  in  each  dose,  and  the  amount  of  poison  recovered  from  the 
viscera  agreed  remarkably  closely  with  this  result. 

2  The  most  successful  antidote  for  strychnine  is  the  persistent  inhalation  of 
chloroform  as  often  as  the  spasms  come  on.  Chloral  hydrate,  in  a  dose  of  30 
grains,  has  proved  highly  efficacious  on  several  occasions,  in  some  instances 
the  cramps  being  wholly  prevented,  while,  on  the  other  hand,  no  narcotic 
action  of  the  antidote  was  manifested.  Injection  of  morphine  has  proved 
similarly  successful.  Tannin  and  animal  charcoal  are  of  little  value  ( Year-Book 
Pharm.,  1890,  page  389).  Formyl-paraphenethidine  (page  85)  has  been  re- 
commended as  an  antidote  for  strychnine  {Pharm.  Zeit.,  1889,  page  625). 

^  The  strychnine  is  used  as  nitrate  in  240  parts  of  water  ( =  2  grains  to  the 
ounce)  mixed  with  a  little  glycerin.  Twenty  minims  should  be  injected  every 
10  to  20  minutes  until  all  the  snake-poison  symptoms  have  disappeared  and 
slight  muscular  spasms  are  observed.  A  grain  or  more  of  strychnine  may  be 
required  in  the  course  of  a  few  hours.  Out  of  about  one  hundred  cases  treated 
in  this  way,  some  of  them  at  the  point  of  death,  byDr  Mueller  of  Yackan- 
dandah,  Victoria,  there  was  only  one  failure,  and  that  arose  from  the  injections 
being  discontinued  after  1^  grain  of  strychnine  had  been  employed  {Pharm. 
Jour.,  [3],  xxi.  1139). 

*  In  a  case  in  the  author's  experience,  the  stomach  presented  such  an  appear- 
ance as  to  suggest  the  presence  of  arsenic  or  other  irritant  poison  ;  but  no 
mineral  poison  could  be  detected.  That  d^ath  was  due  to  administration  of  a 
vermin-killer  containing  strychnine  was  subsequently  fully  proved  by  analysis 
and  admitted  by  the  murderer). 


374  ISOLATIOK^  OF  STRYCHNINE. 

most  characteristic  appearance  is  the  intense  congestion  of  the 
brain  and  spinal  cord,  often  accompanied  with  considerable  effusion 
of  blood. 

For  the  detection  of  strychnine  in  the  dead  body,  the  following 
method  should  be  used,  the  portions  of  the  body  operated  upon 
being  chosen  according  to  the  manner  in  which  the  poison  is  likely 
to  have  been  administered.  Thus  it  is  of  no  use  to  search  in  the 
stomach  or  intestines  for  strychnine  injected  hypodermically.  If 
the  poison  has  undergone  absorption,  it  will  most  probably  be  met 
with  in  the  liver,  but  all  parts  supplied  with  blood  and  most  of 
the  secretions  may  contain  small  quantities  of  the  poison.  In 
extreme  cases,  it  is  desirable  to  operate  on  very  considerable 
quantities  of  material,  as  death  may  be  caused  by  so  small  a 
quantity  of  strychnine  that  the  poison  may  be  altogether  missed 
if  this  precaution  be  not  taken. 

The  portions  of  the  body  to  be  tested  for  strychnine  should  be 
cut  into  small  fragments  with  a  pair  of  scissors,  and  then  further 
reduced  by  bruising  in  a  mortar.  The  product  is  then  treated 
with  rectified  spirit,  mixed  with  about  1  part  in  20  of  acetic 
acid.  This  coagulates  the  albuminoids,  while  allowing  of  the 
complete  solution  of  the  strychnine.  After  a  few  hours  the  liquid 
should  be  strained  through  muslin,  and  the  clarified  filtrate  passed 
through  a  paper  filter.  The  clear  liquid  is  next  evaporated  nearly 
to  dryness,  diluted  with  water,  and  again  filtered.  The  filtrate  is 
once  more  evaporated  to  dryness,  and  the  residue  thoroughly  ex- 
tracted with  strong,  and  preferably  absolute,  alcohol.  The  liquid 
is  filtered,  the  alcohol  removed  by  evaporation,  and  a  small 
quantity  of  water  added.  The  solution  is  placed  in  a  tapped 
separator,  diluted  to  about  20  c.c.  with  water,  and  a  few  drops  of 
hydrochloric  or  dilute  sulphuric  acid  added.  An  equal  measure  of 
ether  is  next  added,  and  the  whole  well  shaken.  On  standing  a  few 
minutes,  the  ether  will  separate  on  the  surface,  when  the  aqueous 
liquid  should  be  withdrawn  through  the  tap,  and  the  ether  then 
run  off  into  a  separate  vessel.^  The  aqueous  liquid  is  then  returned 
to  the  separator,  and  about  30  c.c.  of  a  mixture  of  equal  volumes 
of  ether  and  chloroform  added.  Enough  ammonia  to  render  the 
liquid  distinctly  alkaline  is  next  added,  and  then  the  whole  imme- 
diately shaken  thoroughly  for  about  a  minute.  On  coming  to  rest, 
the  aqueous  liquid  will  tend  to  separate  from  the  mixed  chloro- 

^  This  preliminary  treatment  of  the  acidulated  solution  with  ether  is  very 
important.  It  eflFects  a  separation  of  glucosides,  traces  of  fat,  essential  oils, 
and  other  matters  which  otherwise  would  contaminate  the  strychnine.  In 
some  cases  it  is  desirable  to  repeat  the  agitation  with  a  mixture  of  eq[ual 
measures  of  chloroform  and  ether. 


DETECTION  OF  STRYCHNINE.  375 

form  and  ether,  which  has  a  density  of  about  I'l.  If  tolerably- 
free  from  extractive  matter,  it  will  float  on  the  surface  of  the 
ether-chloroform,  but  if  largely  charged  with  sugar  or  other  soluble 
matter,  it  may  be  equally  dense  with  the  solvent,  or  even  collect 
at  the  lower  part  of  the  separator.  If,  from  the  presence  of 
extractive  matters  or  for  other  reason,  the  liquids  do  not  readily 
separate,  water  or  ammonia  should  be  added,  so  as  to  reduce  the 
density  of  the  aqueous  liquid.  An  alternative,  and  perhaps  pre- 
ferable plan,  is  the  gradual  addition  of  ether,  with  cautious 
agitation,  till  the  solvent  separates  readily  at  the  surface  of  the 
aqueous  liquid.^ 

When  the  division  of  the  contents  of  the  bulb  into  two  layers 
is  complete,  the  strata  are  separated  from  each  other  by  means  of 
the  tap.  If  quantitative  results  are  required,  it  may  be  desirable 
to  agitate  the  aqueous  liquid  with  a  fresh  quantity  of  ether-chloro- 
form. The  solution  of  the  alkaloid  in  the  ether-chloroform  is 
passed  through  a  small  paper  filter,  if  necessary,  and  then 
evaporated  to  dryness  at  a  steam-heat  in  the  manner  described  on 
page  369.  The  residue  obtained  may  then  be  examined  for 
strychnine  by  the  tests  given  on  page  364  e^  seq.  If  strychnine 
be  present,  the  solution  of  the  residue  in  alcohol  will  have  a 
marked  and  persistent  bitter  taste,  especially  noticeable  at  the 
back  of  the  tongue.  The  most  delicate  and  characteristic  chemical 
reaction  of  strychnine  is  the  oxidation-test  described  on  page  368. 
Reactions  6,  7,  and  8,  and  the  production  of  crystals  of  strychnine 
as  described  in  1,  are  also  valuable  as  confirmatory  tests,  and 
should  never  be  omitted  if  the  material  at  disposal  be  sufficient 
for  their  performance.  The  bitter  taste,  however,  in  conjunction 
with  a  distinct  reaction  by  the  characteristic  oxidation-test,  may 
usually  be  regarded  as  ample  proof  of  the  presence  of  strychnine, 
provided  the  absence  of  interfering  substances  has  been  ensured 
by  the  previous  treatment.  The  ptomaine,  stated  by  C.  A  m  t  h  o  r 
(page  371)  to  give  a  colour-reaction  simulating  that  of  strychnine, 
can  only  be  present  when  putrefaction  has  taken  place,  and  its 
formation  must  be  very  rare,  or  it  would  have  been  met  with  in 
the  numerous  cases  in  which  no  alkaloidal  substance  has  been 
detected. 

Blood  should  be  examined  for  strychnine  by  diluting  it  with 
an  equal  bulk  of  water,  adding  a  little  acetic  acid,  boiling  for  a 

^  This  alternative  is  preferable  to  the  addition  of  chloroform,  which,  if  used 
in  too  large  a  proportion,  will  only  separate  from  the  dense  aqueous  liquid 
with  extreme  difficulty.  The  advantage  s,i  employing  a  mixture  of  ether  and 
chloroform,  rather  than  either  solvent  singly,  has  been  pointed  out  by  the 
author  {Analyst^  vi.  141),  though  its  use  did  not  originate  with  him. 


376  PREPARATIONS  OF  STRYCHNINE. 

short  time,  filtering,  and  evaporating  the  filtrate  nearly  to  dryness. 
The  residue  is  taken  up  with  alcohol,  and  the  solution  treated  as 
already  described. 

From  urine,  strychnine  may  be  directly  extracted  by  agitating 
the  fluid  with  ammonia  and  ether-chloroform. 

Dialysis  through  parchment-paper  is  an  efficient  and  occasion- 
ally a  convenient  means  of  separating  strychnine  from  organic 
matter.  The  finely-divided  tissue  should  be  suspended  in  water, 
to  which  some  alcohol  and  acetic  acid  have  been  added.  Dis- 
tilled water  should  be  used  on  the  other  side  of  the  membrane, 
and  changed  at  intervals  of  twelve  hours.  After  thirty-six  to 
forty-eight  hours  the  dialysate  may  be  evaporated  to  dryness,  and 
treated  with  alcohol,  &c.,  as  described  on  page  374. 

It  has  not  unfrequently  happened  that  a  post-mortem  analysis 
has  failed  to  detect  strychnine  in  corpses  almost  certainly  contain- 
ing it.  This  result  has  probably  been  due  in  most  cases  to  the 
use  of  defective  methods  of  analysis,  or  to  the  search  being 
restricted  to  too  small  quantities  of  material  or  to  wrong  parts  of 
the  body.  Occasionally,  failure  has  probably  been  due  to  an 
elimination  of  the  poison  during  life,  especially  in  cases  in  which 
death  has  resulted  from  a  minimum  dose.  Strychnine  does  not 
undergo  decomposition  in  the  dead  body,  and  has  been  detected 
several  years  after  death.^  Hence,  if  elimination  has  not  occurred 
prior  to  death,  strychnine  ought  to  be  found  by  the  toxicologist. 

Preparations  of  Strychnine. 

The  only  preparation  of  strychnine  recognised  in  the  British 
Pharmacopoeia  is  a  solution  of  the  hydrochloride,  which,  as  met 
with  in  commerce,  is  not  so  constant  in  strength  as  is  desirable. 

JEaston's  Syrup  is  a  widely-used  remedy,  consisting  of  a  syrup 
of  the  phosphates  of  iron,  quinine,  and  strychnine.  Its  omission 
from  the  British  Pharmacopoeia  is  lamentable,  and  results  in  con- 
siderable variation  in  the  composition  of  the  preparations  sold 
under  its  name.  According  to  Squire  {Companion  to  the  British 
Pharmacopoeia),  when  prepared  according  to  Dr  Easton's  formula, 
the  syrup  contains  "about  1  grain  phosphate  of  iron,  1  grain 
phosphate  of  quinine,  and  ^  grain  phosphate  of  strychnine  in 
each  fluid  drachm." 

1  The  author  has  had  no  difficulty  in  detecting  strychnine  in  a  stomach 
preserved  in  spirit  for  six  years.  A  portion  of  the  untreated  stomach  and 
liver  from  the  same  person  (who  picked  up  in  a  field  and  ate  an  egg  poisoned 
with  strychnine)  was  kept  in  a  jar,  the  mouth  of  which  was  closed  by  a  bag 
containing  wood -charcoal.  On  opening  the  jar  after  six  years,  the  whole  of 
the  contents  were  found  to  have  disappeared,  with  the  exception  of  a  small 
quantity  of  dust,  in  which  abundance  of  strychnine  was  detected. 


EASTON  S   SYRUP. 


377 


The  following  is  the  range  of  variation  observed  by  D  a  v  i  e  s  and 
Schmidt  {Year-Book  Pharm.,  1883,  page  575)  in  ten  samples 
of  Easton's  Syrup  of  commerce  : — 


Squire's 
Formula. 

B.P. 

Committee's 
Formula. 

Found. 

Highest. 

Lowest. 

Average. 

Quinine       phosphate, 

QU3(H3P04)2, 

Ferrous       phosphate, 
Free  phosphoric  acid, 
Strychnine,  . 
Specific  gravity, 

6-87 

5-30 

38-03 

1-0 

6-0 
8-0 
50-0 
I'O 

7-83 
12-32 
49-24 

3-0 

1-331 

1-57 
0-97 
19-36 
0-6 

1-288 

5-09 

6-91 

34-38 

1-0  to  1-14 

1-^98 

Grains  per 
fluid  oz. 

»» 

Grains  per 
4  fluid  oz. 

The  following  analyses  of  commercial  Easton's  syrup  have  been 
published  by  J.  G.  Wilson  (Fharm.  Jour.,  [3],  xix.  753)  : — 


A. 

B. 

V. 

D. 

E. 

Quinine  phosphate. 
Ferrous  phosphate. 
Phosphoric  acid,      .... 
Strychnine,      .               ... 

5-75 
7-1 
470 
0-25 

5-75 
7-5 
45-0 
0-25 

5-25 
6-4 
48-0 
0-25 

4-25 
5-0 
310 
0-20 

2-00 
5-0 
26-0 
0-10 

In  analysing  Easton's  syrup  the  iron  may  be  determined  by 
evaporating  5  c.c.  of  the  preparation,  igniting  the  residue,  dis- 
solving the  ash  in  hydrochloric  acid,  and  titrating  the  iron  with 
standard  bichromate  solution  after  reducing  it  to  the  ferrous  state. 

The  free  phosphoric  acid  may  be  determined  by  titration  of  10 
c.c.  with  methyl-orange  and  semi-normal  caustic  soda.  The  neutral 
point  is  attained  when  NaHgPO^  is  formed. 

The  alkaloids  are  determined  by  diluting  10  c.c.  of  the  syrup 
with  twice  its  measure  of  water,  adding  some  citric  acid  and  excess 
of  ammonia,  and  agitating  twice  with  ether-chloroform.^  From 
the  weight  of  the  residue  left  on  evaporating  the  solution,  a  deduc- 
tion of  0'0057  gramme  should  be  made  for  the  strychnine  present, 
the  remainder  being  regarded  as  quinine.  An  actual  separation 
can  be  made  by  precipitating  the  strychnine  from  a  strongly  acid 
solution  by  potassium  ferrocyanide,  as  described  on  page  367. 

Another  method  of  separating  the  strychnine  and  quinine  of 


*  From  the  aqueous  liquid  the  total  phosphoric  acid  may  be  thrown  down 
■by  magnesia  mixture 


378  easton's  syrup. 

Easton's  syrup  is  to  dissolve  the  ether-chloroform  residue  obtained 
as  above  in  about  10  c.c.  of  water  acidulated  with  a  few  drops  of 
sulphuric  acid.  The  solution  is  neutralised  by  ammonia  and  mixed 
with  excess  of  ammonium  oxalate.  After  standing  twenty-four 
hours,  the  precipitated  oxalate  of  quinine  is  filtered  off,  the  mother- 
liquor  removed  by  gentle  pressure,  and  the  precipitate  washed  once 
with  a  little  cold  water.  It  is  then  dried  at  100°  and  weighed.^ 
Its  weight,  multiplied  by  '878,  gives  the  quinine  in  the  quantity 
of  the  sample  operated  on.  The  filtrate  and  wash-water  are  then 
treated  with  ammonia,  shaken  with  ether-chloroform,  and  the  dis- 
solved alkaloid  recovered  as  usual  by  evaporation  of  the  solvent. 
The  residue  of  alkaloid  (consisting  of  strychnine,  any  amorphous 
alkaloid,  and  a  mere  trace  of  quinine)  should  be  next  twice  treated 
with  3  c.c.  of  washed  ether,  which  dissolves  the  amorphous  alkaloid 
(and  quinine),  leaving  the  strychnine  almost  wholly  undissolved. 

For  the  determination  of  the  small  proportion  of  strychnine  con- 
tained in  Easton's  syrup,  Davies  and  Schmidt  recommend  the 
following  colorimetric  process  devised  by  O.  E  c  k  e  n  s  t  e  i  n.  The 
alkaloidal  residue  from  10  c.c.  of  syrup  was  dissolved  in  31*25  c.c. 
of  water  acidulated  with  1  c.c.  of  normal  sulphuric  acid,  and 
5  drops  of  the  resultant  solution  were  added  to  4  c.c.  of  concen- 
trated sulphuric  acid  tinted  yellow  with  potassium  bichromate. 
The  colour  produced  after  standing  five  minutes  was  then  com- 
pared with  the  colour  produced  by  known  quantities  of  a  very 
dilute  solution  of  strychnine  of  known  strength,  in  the  same  sul- 
phuric acid  coloured  with  bichromate.  For  quantitative  purposes 
the  method  leaves  much  to  be  desired. 

Easton's  syrup  is  liable  to  give  a  deposit  which  sometimes  con- 
tains quinine,  and  in  other  cases  appears  to  be  simply  ferric  phos- 
phate. The  tendency  to  deposit  is  often  prevented  by  addition  of 
a  small  quantity  of  hydrochloric  acid. 

Vermin-killers.  An  inquiry  into  the  composition  of  various 
commercial  vermin-killers  containing  strychnine  was  made  by  the 
author  in  1889  {Year-Book  Pharm.,  1889,  page  434).  The  results 
showed  them  to  consist  of  a  mixture  of  strychnine  with  rice  or 
wheat-starch,  usually  more  or  less  coloured.  Ultramarine  was  the 
most  usual  colouring  agent,  but  prussian  blue  was  met  with  in 
four  preparations  out  of  seventeen  examined,  in  one  case  the 
powder  containing  both  ultramarine  and  prussian  blue.     Carmine 


*  The  mode  of  operating  described  in  the  text  is  due  to  B.  W.  D  wars. 
It  would  probably  be  better  to  wash  the  precipitate  produced  by  ammonium 
oxalate,  and  then  extract  the  quinine  in  the  free  state  by  agitating  the  pre- 
cipitate with  ammonia  and  ether. 


VERMIN-KILLERS.  379 

was  the  colouring-matter  of  two  preparations  and  soot  of  one.^ 
lu  one  instance,  no  colouring-matter  whatever  was  present.^ 

Ultramarine  is  readily  recognised  in  a  vermin-killer  by  the 
peculiar  shade  of  blue  it  communicates  to  the  powder,  and  by  the 
colour  being  wholly  destroyed  by  agitation  with  dilute  acid.  If  a 
little  of  the  powder  be  placed  on  a  silver  coin  and  moistened  with 
dilute  acid,  a  brown  stain  will  be  produced  on  the  coin  by  the 
sulphuretted  hydrogen  liberated  from  the  ultramarine.  Ultra- 
marine retains  its  blue  colour  after  ignition,  whereas  prussian  blue 
leaves  a  brownish  residue  of  oxide  of  iron,  and  indigo  is  more  or 
less  perfectly  consumed,  according  to  its  purity.  A  decidedly  ferru- 
ginous ash  is  left  by  some  specimens  of  indigo.  Prussian  blue  and 
indigo  are  unaffected  by  dilute  hydrochloric  acid.  If  the  residue 
left  after  heating  the  powder  with  dilute  hydrochloric  acid  be 
washed  and  treated  with  caustic  soda  solution,  it  will  be  unaffected 
if  composed  of  indigo ;  but  prussian  blue  will  be  turned  brown, 
and  the  filtered  liquid  wiU  contain  a  ferrocyanide,  and  hence  will 
yield  a  blue  or  green  precipitate  or  coloration  when  it  is  acidulated 
with  hydrochloric  acid  and  ferric  chloride  added. 

The  colour  of  a  vermin-killer  should  not  merely  serve  as  a 
danger-signal,  but  be  so  chosen  as  to  facilitate  its  detection  in 
cases  where  it  has  been  used  for  the  purpose  of  suicide  or  murder. 
In  a  case  in  which  the  author  was  concerned,  a  murderer  would 
probably  have  escaped  conviction  but  for  the  detection  of  the  blue 
colouring-matter  in  the  stomach  of  his  victim,  which  served  to 
connect  him  with  the  administration  of  the  poison.^ 

1  This  preparation  consisted  of  strychnine,  5 "8  per  cent;  native  barium  car- 
bonate, 45 '0  per  cent. ;  and  wheat-flour  and  soot,  49*2  per  cent.  The  object  of 
the  combination  is  not  evident. 

2  Such  a  colourless  preparation  is  highly  dangerous.  Teething  powders  are 
so  generally  coloured  pink  that  they  are  not  unfrequently  asked  for  as  "pink 
powders,"  and  gray  powders  are  equally  common.  The  blue  colouring-matters 
present  considerable  advantages  over  such  pigments  as  soot  and  carmine,  since 
no  food,  drink,  or  medicine  has  naturally  a  blue  colour,  and  hence  the  tint 
at  once  attracts  attention. 

'  Soot  is  unsuitable  for  colouring  vermin-killers,  as  the  identification  of 
minute  particles  of  carbon  is  diflBcult  or  impossible  when  mixed  with  food.  Of 
the  blue  colouring-matters  practically  available,  ultramarine  is  too  readily 
destroyed  by  dilute  acids  and  by  the  gastric  juice,  though  it  has  the  advantage 
of  being  readily  detected,  and  of  being  undestroyed  by  ignition.  Prussian 
blue  is  unaffected  by  acids,  and  not  very  readily  affected  by  dilute  alkaline 
liquids.  Indigo  resists  alkalies  still  better,  and  is  not  affected  by  acids,  except 
nitric  acid,  though  it  is  at  once  bleached  I5y  oxidising  agents,  and  is  also 
decolorised  by  alkaline  reducing  agents.  In  minute  quantity  it  is  less  easily 
recognised  than  prussian  blue.     A  mixture  of  the  three  pigments  would  be 


380  VERMIN-KILLERS. 

The  toxicity  of  vermin-killers  varies  within  wide  limits.  Of 
the  samples  examined  by  the  author,  the  weight  of  strychnine 
contained  in  a  packet  of  the  powder  varied  from  0"60  to  4*18 
grains,  the  retail  price  in  each  case  being  3d.  The  proportion 
of  strychnine  ranged  from  4*2  to  41*8  per  cent.^ 

Strychnine  can  be  determined  in  vermin-killers  by  exhausting 
a  known  weight  of  the  dry  powder  with  chloroform  or  benzene, 
and  weighing  the  alkaloidal  residue  left  on  evaporating  the  solvent. 
The  insoluble  portion  must  be  examined  by  the  taste  and  oxida- 
tion-test, to  ensure  complete  extraction  and  the  absence  of  a 
salt  of  strychnine  insoluble  in  the  solvent  used.  An  alternative, 
and  in  many  respects  preferable,  method  is  to  treat  the  vermin- 
killer  with  cold  water  acidulated  with  acetic  acid,  until  the 
residual  powder  has  no  bitter  taste,  and  gives  no  coloration  by 
the  oxidation-test.  The  solution  is  then  treated  with  excess  of 
ammonia,  and  the  strychnine  extracted  by  ether-chloroform,  which 
is  separated,  evaporated  to  dryness,  and  the  residue  weighed. 

Of  vermin-killers  containing  strychnine.  Battle's  preparation 
is  the   best  known,   and    most  extensively  used.      The   suicides 

preferable  to  any  one  or  two  of  them.  "The  most  suitable  pigment  for  colour- 
ing vermin-killers  would  be  chrome-green  (CrgOg).  In  it  we  have  a  bright 
green  pigment  of  high  colouring  power,  quite  insoluble  in  water  and  dilute 
acid  and  alkaline  liquids.  It  is  wholly  permanent  under  all  imaginable  con- 
ditions, and  is  not  affected  by  ignition.  Chromium  is  not  a  natural  con- 
stituent of  the  body,  is  not  used  internally  as  a  medicine,  and  is  not  liable  to 
be  present  accidentally,  even  in  traces,  in  any  beverage  or  article  of  food.  It 
can  be  detected  and  determined  with  ease  and  certainty,  even  when  present  in 
very  minute  quantity.  Owing  to  its  insolubility,  oxide  of  chromium  would 
remain  wholly  unabsorbed  if  taken  internally.  Hence,  if  it  were  added  to 
preparations  of  strychnine,  &c.,  in  a  definite  and  invariable  proportion,  an 
estimate  of  the  minimum  amount  of  poison  taken  by  a  deceased  person  could 
be  arrived  at  by  determining  the  amount  of  chromium  contained  in  the  alimen- 
tary canal,  even  though  the  poison  itself  had  been  wholly  absorbed  or  decom- 
posed ;  and  this  could  be  effected  with  equal  ease  and  certainty  after  prolonged 
inhumation,  or  even  after  cremation  of  the  body." — A.  H.  Allen  {Year-Book 
Pharm.,  1889,  page  439). 

^  It  does  not  follow  that  the  vennin-killer  which  contains  the  greatest 
weight  or  the  largest  proportion  of  strychnine  is  the  best  for  its  purpose. 
Clearly,  pure  strychnine  would  be  inefficient,  and  hence  the  object  should  be 
to  compound  a  mixture  which  will  have  the  most  powerful  poisoning  efiect 
compatible  with  its  attractive  and  appetising  character.  To  effect  this,  the 
bitter  taste  of  the  strychnine  should  be  masked  as  far  as  possible,  and  a 
suitable  odorant  should  be  added.  This  object  seems  to  have  been  recognised 
in  one  instance,  for  the  powder  contained  sugar  and  had  a  powerful  smell 
of  assafcetida  and  oil  of  anise.  Most  of  the  vermin-killers  examined  by  the 
author  have  been  odourless. 


BATTLE  S   VERMIN-KILLER. 


381 


due  to  it  amount  to  many  scores,  and  probably  to  hundreds. 
The  colouring-matter  of  Battle's  vermin-killer  appears  to  have 
been  uniformly  prussian  blue ;  but  the  following  table  shows 
that  the  composition  ascribed  to  the  preparation  has  varied  in 
other  respects  at  different  periods  : — 


Authority. 

A.  Swaine 
Taylor. 

A.  J. 

Bernays. 

T.  Steven- 
son. 

A.  H. 
Allen. 

Tardieu. 

Woodman 
and  Tidy.  1 

Date, 

1862. 

1876. 

1882. 

1889. 

Price  of  packet, 

3d. 

3d. 

6d. 

6d. 

... 

... 

Weight  of  powder,  . 

13  grains. 

15  grains. 

25  grains. 

21  -5  grains. 

20  grains. 

Colouring-matter,    . 
Starchy  matter, 
Strychnine ;  grains, 

Prussian 
blue. 
Flour. 

0-75 

Prussian 
lilue. 

Wheat- 

flour. 

1-6 

Prussian 
blue. 

2-5 

Prussian 
blue. 

Wheat- 
flour. 
2-4 

Prussian 
blue. 
Potato- 
starch. 
1-5 

Prussian 
blue. 
Flour. 

Strychnine ;         per 
cent, 

5-8 

10-7 

10-0 

11-2 

7-7 

23-0 

The  inert  matter  of  vermin-killers  usually  consists  of  rice-starch, 
though  in  some  cases  wheat-flour,  and  occasionally  oatmeal,  is 
substituted.  In  one  instance,  the  author  found  both  rice  and 
wheat  starch,  the  powder  being  coloured  with  carmine. 


Brucine.    Brucia.   0231126^204;  or  022Hi8( 00113)2. 

Brucine  occurs  in  association  with  strychnine  in  nux  vomica,  St 
Ignatius'  beans,  and  false  angustura  bark  (page  360).  The  leaves 
of  stryclinos  nux  vomica  are  stated  to  contain  brucine  but  no 
strychnine. 

In  chemical  constitution,  brucine  appears  to  be  a  dimethoxy- 
strychnine.^ 

Brucia  occurs  as  a  bitter,  white,  odourless,  crystalline  or 
amorphous  powder,  or  in  groups  of  very  delicate  needles  or  four- 
sided  prisms,  containing  15*45  per  cent,  of  water  (  =  OggHggNgO^ + 

^Woodman  and  Tidy  state  that  sugar  is  a  constituent  of  Battle's 
vermin-killer.  This  was  certainly  not  the  case  in  1889.  The  proportion  of 
strychnine  (23  per  cent.)  given  by  Woodman  and  Tidy  is  largely  in  excess  of 
that  found  by  other  observers. 

2  Haussen  finds  that  both  strychnine  and  brucine  yield  by  oxidation  with 
chromic  acid  mixture  a  body  containing  Ci6Hi8N2()4,  and  hence  that  the 
difiference  between  the  two  alkaloids  must  be  ^sought  in  the  residues,  C5H4  and 
CyHgOg  respectively,  removed  through  the  oxidation.  The  former  of  these  is 
regarded  as  pointing  to  the  presence  of  a  benzene- nucleus  in  strychnine,  which 
nucleus  in  brucine  is  dimethoxylated. 


382  CHARACTERS   OF   BRUCINE. 

^HgO).-^  When  moderately  heated  the  crystals  melt  and  lose  their 
water.  According  to  Guy,  brucine  melts  at  115°,  and  sublimes 
at  204°  C,  the  sublimate  being  usually  amorphous.  According 
to  Glaus  and  Rdhre,  after  drying  at  150°,  brucine  melts  at 
178". 

Brucine  is  more  soluble  than  strychnine  in  water,  dissolving  in 
1050  parts  of  cold,  and  less  than  half  that  proportion  of  boiling 
water.  In  alcohol  it  dissolves  very  readily,  a  fact  which  is 
employed  to  separate  it  from  strychnine.  Brucine  dissolves  in 
4  parts  of  chloroform,  in  440  of  ether,  in  60  of  benzene,  and  in 
120  of  petroleum  spirit.  It  is  insoluble  in  fixed  caustic  alkalies, 
and  only  sparingly  in  excess  of  ammonia. 

Brucine  is  a  weaker  base  than  strychnine,  but  is  not  extracted 
from  acidulated  solutions  by  immiscible  solvents.  It  resembles 
strychnine  closely  in  its  general  characters,  but  is  less  poisonous, 
from  7  to  10  parts  of  brucine  having  the  same  physiological  effect 
as  1  part  of  strychnine.^  It  is  excreted  far  more  rapidly  than 
strychnine,  so  that  when  given  by  the  stomach  it  produces  little 
effect,  though  it  is  fatal  when  injected  hypodermically  (T.  Lauder 
Brunt  on.  Jour.  Gliem.  Soc,  xlvii.  143).^  Like  strychnine,  it  is 
not  acted  on  readily  by  cold  sulphuric  acid,  or  by  caustic  alkalies. 
It  dissolves  without  decomposition  in  strong  hydrochloric  acid,  and 
forms  readily  crystallisable  and  soluble  salts. 

Gn  passing  nitrogen  trioxide  into  an  alcoholic  solution  of  brucine, 
brucine  nitrate  at  first  separates,  but  again  dissolves,  forming  a 
red  solution  from  which  dinitrobrucine,  G23H24(N02)9l!^2^4' 
separates  as  a  heavy,  granular,  blood-red  precipitate.  By  washing 
with  alcohol  and  ether,  it  is  obtained  as  an  amorphous,  velvety, 
vermillion-coloured  powder,  easily  soluble  in  water,  sparingly  in 
alcohol,  and  insoluble  in  ether.  The  chloroplatinate  is 
obtained  as  a  yellow  precipitate  on  adding  platinic  chloride  to  the 
aqueous  solution  of  dinitrobrucine  (Glaus  and  Rohre,  Ber.j 
xiv.  765). 

Analytical  Gharaotbrs  op  Brucine. 

1.  Brucine  is  precipitated  in  a  free  state  on  adding  an  alkali  to 
the  solution  of   one  of   its  salts,  and  may  then  be  taken  up  by 

^  From  analyses  of  their  platinous  compounds,  Koefoed  is  of  opinion  that 
commercial  brucine  contains  two  homologous  alkaloids. 

2  According  to  Talk,  the  physiological  activity  of  strychnine  is  38^  times 
greater  than  that  of  brucine. 

*  T.  J.  Mays  {Jour.  Physiol.,  viii.  391)  finds  that,  when  frogs  are  poisoned, 
brucine  primarily  affects  the  posterior  and  strychnine  the  anterior  extremities  ; 
convulsions  occur  very  early  and  invariably  before  death  in  strychnine  poison- 
ing, and  very  late  or  frequently  not  at  all  in  brucine  poisoning. 


REACTIONS  OF  BRUCINE.  383 

agitating  the  alkaline  liquid  with  ether- chloroform  in  the  same  way 
as  strychnine  (see  page  364). 

2.  Brucine  forms  a  soluble  chromate,  a  fact  which  is  occasion- 
ally used  to  separate  it  from  strychnine.  A  better  separation  is 
effected  by  crystallising  the  free  alkaloids  from  hot  alcohol,  or  by 
converting  them  into  ferrocyanides  (page  366). 

3.  When  treated  with  concentrated  sulphuric  acid^  and  an 
oxidising  agent,  brucine  does  not  give  the  coloured  products  so 
characteristic  of  strychnine. 

4.  The  most  satisfactory  reaction  of  brucine  is  that  with  nitric 
acid.  On  adding  a  drop  or  two  of  cold  nitric  acid  of  1'42  sp.  gr. 
to  an  ether- chloroform  residue,  or  other  solid  product  containing 
brucine,  a  scarlet  or  blood-red  coloration  is  produced,  which  on 
heating  changes  to  yellowish  red,  and  finally  to  yellow.^  If  the 
mixture  be  now  cooled  and  treated  very  cautiously  with  stannous 
chloride  (or  other  reducing  agent,  such  as  sodium  thiosulphate),  a 
purple  coloration  is  produced,  which  is  destroyed  by  excess  of 
either  nitric  acid  or  the  tin  salt.^ 

The  red  coloration  of  brucine  by  nitric  acid  may  likewise  be 
developed  by  dissolving  the  alkaloid  in  strong  sulphuric  acid  in  a 
test-tube,  and  allowing  nitric  acid  to  run  on  to  the  surface  of  the 
heavier  liquid.  A  red  zone,  passing  to  yellow,  will  be  produced  at 
the  junction  of  the  two  liquids.  If  cold  nitric  acid  be  added  to 
solid  brucine,  so  as  to  develop  the  red  colour,  and  the  moisture  be 
then  largely  diluted  with  water,  a  body  called  kakotelin, 
^2oH22(-^ ^2)2^2^5,  separates  in  yellow  flocks.  The  filtered  liquid, 
after  neutralisation  by  ammonia,  gives  a  precipitate  of  calcium 
oxalate  on  being  treated  with  calcium  chloride.  The  precipitated 
kakotelin  may  be  dissolved  in  dilute  hydrochloric  acid,  and  crystal- 
lised therefrom  in  orange-red  or  yellow  scales. 

The  production  of  a  red  colour  with  nitric  acid,  accompanied  by 
a  formation  of  oxalic  acid  and  yellow  scales  or  crystals,  insoluble 
in  water  but  soluble  in  dilute  acids,  constitutes  a  combined  reaction 
which  is  peculiar  to  brucine. 

5.  Brucine  dissolves  in  chlorine-water  with  red  colour.  On 
evaporation,  dichlorobrucine,  CggHg^ClaNgO^,  remains  as  a 
reddish  brown,  amorphous  mass. 

6.  Potassium  bichromate  throws  down  from  solutions  of  brucine 

*  According  to  some  observers,  strong  sulphuric  acid  imparts  to  brucine  a 
rose  colour,  which  changes  first  to  yellow  and  then  to  yellowish  green. 

2  Stiychnine,  on  the  contrary,  gives  n*  coloration  with  cold  nitric  acid,  but 
developes  a  yellow  colour  on  warming. 

^  The  orange  colour  produced  by  adding  nitric  acid  to  morphia  remains 
unchanged  on  addition  of  stannous  chloride. 


384  NUX   VOMICA. 

salts,  even  when  very  dilute,  a  yellow  precipitate  of  brucine 
chromate,  insoluble  in  acetic  acid,  but  soluble  with  deep  red  colour 
in  strong  nitric  acid.  The  microscopic  appearance  of  brucine 
chromate  is  characteristic,  and,  together  with  its  behaviour  with 
nitric  acid,  distinguishes  the  precipitate  from  all  others  produced  by 
the  reagent. 

7.  The  microscopic  appearances  of  the  precipitates  produced  in 
brucine  solutions  by  platinic  chloride  and  potassium  ferricyanide 
are  also  highly  peculiar. 

8.  Potassium  ferrocyanide  only  slowly  precipitates  acidulated 
brucine  solutions,  and  affords  the  best  means  of  quantitatively 
separating  brucine  from  strychnine  (page  366). 

Nux  Vomica.-^     Poison-nuts.     Quaker  Buttons. 

The  seeds  of  Strychnos  nux  vomica  are  known  by  the  above 
names.  Their  appearance  is  highly  characteristic.  They  have  no 
odour,  but  taste  intensely  bitter.^ 

If  powdered  nux  vomica  seeds  be  moistened  with  water  and 
examined  with  a  low  power,  the  characteristic  fibrous  hairs  can  be 
readily  recognised.  They  acquire  a  yellow  colour  on  adding  iodised 
potassium  iodide,  while  the  rest  of  the  powder  becomes  brown. 
Touched  with  strong  nitric  acid,  the  powder  acquires  an  orange-red 
colour,  gradually  destroyed  on  adding  stannous  chloride. 

JSTux  vomica  contains,  in  addition  to  the  usual  plant-constituents, 
the  poisonous  alkaloids  strychnine  and  b  r  u  c  i  n  e,^  a  glucoside 
called  1 0  g  a  n  i  n,  and  a  peculiar  acid  named  strychnic  or 
igasuric  acid. 

Strychnic  or  Igasuric  Acid  appears  to  be  a  variety  of  tannin. 
It  was  obtained  by  Hohn  (1873)  as  an  amorphous  yellowish- 
white  mass  of  strongly  acid  and  somewhat  astringent  taste.  It 
gives  a  dark  green  coloration  with  ferric  chloride,  a  white  precipitate 
with  lead  acetate,  and  rapidly  reduces  ammonio-nitrate  of  silver. 

1  French  ;  Noix  vomiques.     German  ;  Krdhenaugen,  Brechnuss. 

2  The  powder  of  nux  vomica  has  a  grayish-buff  colour,  and,  in  the  experi- 
ence of  the  author,  has  been  sold  by  a  registered  druggist  in  mistake  for 
jalap.  Death  has  been  caused  by  the  sale  of  nux  vomica  for  liquorice  powder, 
which,  by  artificial  light,  is  of  somewhat  similar  appearance  {Pharm.  Jour., 
[.S],  xvi.  401). 

3  If  a  microscopic  section  of  nux  vomica  be  treated  with  petroleum  spirit  to 
remove  the  fat,  the  parts  containing  brucine  will  then  assume  a  bright  red 
colour  on  being  moistened  with  a  mixture  of  selenic  and  nitric  acids.  To 
detect  strychnine,  the  section  is  treated  in  succession  with  petroleum  spirit 
and  absolute  alcohol  (to  remove  sugar  and  brucine),  and  then  tested  with  a 
solution  of  cerium  sulphate  in  sulphuric  acid  (0.  Lindt,  Ghem.  Centr.,  1884, 
page  498). 


LOGANIN. 


385 


LoGANiN  exists  in  nux  vomica  seeds,  but  more  largely  (4  to  5 
per  cent.)  in  the  pulp  in  which  they  lie  embedded  in  the  fruit. 
Duns  tan  and  Short  (Pharm.  Jour.,  [3],  xiv.  1025)  obtained 
loganin  in  prismatic  crystals  by  cooling  the  liquid  obtained  by  ex- 
hausting this  substance  with  chloroform-alcohol  (4:1).  After  re- 
crystallisation  from  alcohol,  the  crystals  contained  CgsHg^O^^,  an 
empirical  formula  identical  with  that  of  arbutin,  from  which,  how- 
ever, loganin  is  distinguished  by  its  much  higher  melting-point  (above 
200°  C),  and  by  not  yielding  quinol  with  dilute  sulphuric  acid. 

Loganin  is  readily  soluble  in  water  and  alcohol,  but  less  so  in 
ether,  chloroform  and  benzene.  It  developes  no  colour  with  nitric 
acid  or  other  oxidising  agents,  and  the  aqueous  solution  is  not 
affected  by  solutions  of  lead,  iron  or  silver,  and  does  not  reduce 
Fehling's  solution.  When  gently  warmed  with  strong  sulphuric 
acid,  loganin  gives  a  fine  red  colour,  changing  to  purple  on  stand- 
ing. When  boiled  with  dilute  sulphuric  acid,  it  yields  a  reducing 
glucose  and  loganetin,  which  latter  body  behaves  with 
solvents  and  reagents  very  similarly  to  loganin  itself. 

For  the  assay  of  nux  vomica,  D  u  n  s  t  a  n  and  Short  (Pharm. 
Jour.,  [3],  xiii.  665,  1055)  recommend  that  5  grammes  of  the 
finely-divided  seeds  (previously  dried  at  100°  C.)  should  be  ex- 
hausted in  a  Soxhlet  tube  or  its  equivalent,  for  one  or  two  hours, 
with  a  mixture  of  40  c.c.  of  chloroform  and  10  of  alcohol.^  The 
solution  is  agitated  with  25  c.c.  of  dilute  sulphuric  acid  (5  per  cent.), 
and  the  chloroform  separated  and  again  agitated  with  10  c.c.  of 
dilute  acid.  The  separated  acid  solutions  are  filtered,  if  necessary, 
rendered  alkaline  with  ammonia,  and  shaken  twice  with  chloroform, 
using  15  c.c.  each  time.  The  chloroformic  solution  is  separated, 
filtered,  evaporated,  and  the  residue  dried  at  100°  for  about  an  hour, 
or  till  constant  in  weight.     The  following  results  were  obtained  : — 


Description  of  Sample. 

Date  of 
Collection. 

Total  Percentage 
of  Alkaloids. 

Bombay,  fine,    . 
Bombay,  ordinary,     . 
Bombay,    . 
Cochin,      . 
Cochin, 
Madras,      . 
Madras, 

1877 
1877 
1883 
1887 
1883 
1877 
1883 

3-46 
3-14 
3-90 
3-04 
3-60 
2-74 
3-15 

Average, 

3-29 

^  This  mixture  is  described  by  the  authors  as  one  containing  25  per  cent,  of 
alcohol. 

VOL.  III.  PART  II.  2  B 


ASSAY   OF   NUX   VOMICA. 

The  alkaloid  in  powdered  commercial  nux  vomica  ranged  from 
2*56  to  3-57  per  cent.^ 

Ether-chloroform  may  be  advantageously  substituted  for  un- 
mixed chloroform  in  the  foregoing  process,  and  the  alkaloids 
may  be  conveniently  titrated  with  a  standard  mineral  acid  and 
methyl-orange  instead  of  being  weighed.  One  c.c.  of  decinormal 
acid  neutralises  0'0364  gramme  of  a  mixture  of  brucine  and  strych- 
nine in  molecular  proportions  (334 :  394).  When  desired,  the 
strychnine  and  brucine  may  be  separately  determined  as  described 
on  page  367. 

ExTEiACT  OF  Nux  YoMiCA,  B.P.,  is  directed  to  be  prepared  by 
exhausting  the  dried  and  powdered  seeds  with  somewhat  diluted 
spirit  (4:1),  and  evaporating  the  filtered  liquid.  Formerly  the 
extract  varied  considerably  in  strength,  twelve  specimens  of  the 
commercial  article  examined  by  D  u  n  s  t  a  n  and  Short  in  1884 
{Pharm.  Jour.,  [3],  xiv.  443)  containing  proportions  of  total 
alkaloids  ranging  from  10*32  to  17"54  per  cent.;  while  the  ratio 
of  strychnine  to  brucine  varied  from  1:1  up  to  1  : 1'79.2  On  the 
other  hand,  the  proportion  of  water  only  varied  between  13'6  and 
19*7  per  cent.^ 

In  the  Pharmacopoeia  of  1885,  the  extract  is  directed  to  be 
standardised  so  as  to  contain  15  per  cent,  of  total  alkaloids.  For 
its  assay,  10  grains  of  the  extract  are  directed  to  be  dissolved  in 
J  oz.  of  water,  heating  gently  if  necessary,  and  a  solution  of  30 
grains  of  sodium  carbonate  in  J  oz.  of  water  added.  The  solution 
is  then  agitated  with  J  oz.  of  chloroform,  which  extracts  the 
alkaloids.  This  treatment  should  be  repeated  {Pharm.  Jour.,  [3], 
xix.  625),  after  which  the  chloroform  is  shaken  with  dilute  acid, 
and  this  solution  extracted  with  chloroform  and  ammonia  in  the 
manner  already  described  (page  385). 

As  strychnine  is  greatly  more  active  than  brucine,  and  the 
relative  proportions  of  the  two  alkaloids  in  the  extract  are  by  no 
means  constant,  it  is  questionable  whether  it  would  not  be  pre- 

^  Powdered  nux  vomica  has  frequently  been  dried  at  a  temperature  above 
100°,  in  which  case  the  chloroform-alcohol  extract  often  contains  colouring- 
matter  which  ultimately  contaminates  the  alkaloid.  In  such  cases  the  brown 
colour  may  be  removed  by  agitating  the  chloroform-alcohol  solution  with  an 
aqueous  solution  of  crystallised  sodium  carbonate  (5  per  cent. )  before  treating 
it  with  dilute  acid. 

^Beckurts  {Pharm.  Jour.,  [3],  xx.  341)  found  in  five  samples  of  nux 
vomica  extract  the  ratio  of  strychnine  to  brucine  varied  only  between  43 :  57 
and  54  :  46. 

8  The  absence  of  relation  between  the  total  extractive  matter  and  the  alka- 
loids of  nux  vomica  renders  the  official  method  of  standardising  the  extract 
very  unsatisfactory. 


PREPARATIONS  OF  NUX  VOMICA.  387 

ferable  to  ascertain  the  proportion  of  actual  strychnine  rather  than 
that  of  the  total  alkaloids. 

G.  F.  Schacht  {Pharm.  Jour.,  [3],  xiv.  851)  recommends 
for  the  rapid  assay  of  nux  vomica  extract  that  1  gramme  be  dis- 
solved in  30  c.c.  of  water,  the  solution  acidulated  with  1  c.c.  of 
hydrochloric  acid,  warmed  gently  for  half  an  hour,  and  allowed  to 
•cool.  It  is  then  filtered  and  made  up  to  100  c.c.  Ten  c.c.  of 
this  solution  is  then  titrated  with  ^  Mayer's  solution  (page  139), 
■each  c.c.  of  which  represents  0'00184  gramme  of  mixed  strychnine 
and  brucine.^  The  results  by  this  process  are  stated  to  agree 
•closely  with  those  obtained  by  the  gravimetric  method. 

Nux  vomica  extract  contains  from  9  to  about  20  per  cent,  of 
water,  and  some  specimens  lose  and  others  gain  weight  on  exposure. 

Tincture  of  Nux  Vomica,  B.P.,  is  directed  to  be  prepared  by 
dissolving  the  extract  in  slightly  diluted  spirit,  so  as  to  contain  1  grain 
of  total  alkaloids  in  each  fluid  ounce;  equivalent  to  0*229  grain 
per  1 00  measures.  D  u  n  s  t  a  n  and  Short  (  Year-Buok  Pharm., 
1883,  p.  476)  found  the  specific  gravity  of  twelve  commercial  tinc- 
tures, obtained  from  the  principal  London  manufacturers,  to  vary 
from  '8377  to  '8552  ;  the  proportion  of  strychnine  from  0*046  to 
0*131,  with  an  average  of  0*080  per  cent.;  the  brucine  from  0*075  to 
0*239,  averaging  0*130  per  cent. ;  and  the  total  alkaloid  from  0*124 
to  0*360,  with  an  average  of  0*218  per  cent.  Before  1885,  when 
the  tincture  was  directed  to  be  prepared  from  a  duly  standardised 
•extract,  its  strength  was  very  variable.^  The  tincture  of  nux  vomica 
may  be  assayed  by  evaporating  the  spirit  from  50  c.c,  treating  the 
residue  with  dilute  sulphuric  acid  and  chloroform,  separating  the 
«,cid,  and  extracting  the  alkaloids  by  ammonia  and  chloroform. 

Alkaloids  of  Curare. 

The  Indian  arrow-poison^  known  as  curare,  curari, 
wourali,  woorara,  or  urari  is  a  poisonous  extract  prepared 

1  The  solution  is  prepared  with  1*355  gramme  of  mercuric  chloride  and  4*98 
of  potassium  iodide  in  the  litre. 

-  The  preparation  of  the  tincture  of  nux  vomica  from  a  standardised  extract 
has  apparently  failed  to  secure  uniformity  in  its  composition  ;  for  of  twenty- 
four  samples  of  the  commercial  tincture  purchased  by  N,  H.  Martin  in  1886, 
nine  months  after  the  publication  of  the  new  edition  of  the  Pharmacoposia, 
eleven  showed  by  their  pale  yellow  colour  that  they  had  been  prepared  by  the 
old  process  from  the  seeds,  and  contained  from  0*119  to  0-288  per  cent,  of  total 
alkaloids  ;  while  the  percentage  of  total  alkaloids  in  the  thirteen  samples 
which  by  their  light  brown  colour  showed  they  had  been  prepared  from  the 
•extract,  ranged  from  0*196  to  0"313  per  cent.  {Year-Book  Pkarm.,  1886, 
page  507). 

^  The  intensely  active   arrow-poison   used   by  the  pigmies   met  with  by 


388  CURAKE. 

from  the  bark  of  Strychnos  toxifera,  a  native  of  Guiana,  together 
with  other  vegetable  extracts. ^  It  occurs  in  commerce  as  a  black, 
shining,  brittle,  resinoid  mass,  of  an  intensely  bitter  taste.  About 
83  per  cent,  is  soluble  in  water,  and  79  in  diluted  spirit.  A  mixture 
of  glycerin  and  diluted  spirit  dissolves  85  per  cent.,  but  it  is  only 
slightly  acted  on  by  ether  or  chloroform,  even  in  presence  of  a  free 
alkali.  Curare,  as  imported,  varies  much  in  strength,  and  often  con- 
tains calcium  carbonate  and  phosphate.  It  is  exceedingly  poisonous, 
and  should  be  handled  with  the  utmost  care.  Curare  should  never 
be  allowed  to  come  in  contact  with  a  cut  or  scratch,  and,  indeed, 
should  never  be  touched  with  the  naked  fingers,  or  powdered  or 
manipulated  in  the  dry  state. 

"  Much  doubt  exists  as  to  the  true  nature  of  woorara.  According 
to  W  a  t  e  r  1 0  n  it  is  prepared  from  several  different  plants,  two 
species  of  poisonous  ants,  and  the  fangs  of  certain  snakes ;  while 
Schomburgk  states  that  it  consists  of  vegetable  matter  alone, 
and  chiefly  of  the  bark  of  Strychnos  toxifera.  .  ,  .  That  there  are 
at  least  several  varieties  of  this  substance  current  among  the  dif- 
ferent tribes  of  Indians  seems  to  be  fully  established  .  .  . ;  and  it 
is  even  probable  that  each  tribe  has  its  own  method  of  preparing  the 
poison  "  (T.  G.  W  0  r  m  1  e  y,  Micro-Ohemistiy  of  Poisons). 

Curarine  exercises  both  a  paralysing  and  tetanising  action,  but  it 
appears  to  owe  its  chief  poisonous  properties  to  its  action  on  the 
nerves  of  motion,  which  it  paralyses,  so  that  an  animal  under  its 
influence  dies  of  suffocation  from  paralysis  of  the  muscles  of  the 
chest.  Hence  its  physiological  effects  closely  resemble  those 
produced  by  methyl-strychnine.  According  to  J.  T  i  1 1  i  e,  when 
the  difficulties  besetting  the  examination  of  the  action  of  curare 
on  the  spinal  cord  are  avoided,  curare  produces  tetanus  just  like 
strychnine.  Curare  appears  not  to  act  as  a  poison  when  taken  into 
the  stomach,  but  when  employed  as  a  hypodermic  injection  "015 
grain  has  been  found  fatal  to  a  rabbit,  and  '004  grain  to  a  frog. 
If,  after  administration  of  curare,  life  be  maintained  by  artificial 
respiration,  symptoms  of  diabetes  mellitus  are  observed,  and  the 
urine  is  found  to  contain  sugar. 

Neither  strychnine  nor  brucine  has  been  detected  in  curare,  and 
that  the  paralysing  effects  of  the  preparation  are  not  due  to  methyl- 
strychnine  is  apparently  proved  by  the  superior  toxicity  of  the 
vegetable  extract.  J.  Tillie  (Jour.  Anat.  and  Physiol.,  1890) 
attributes  both  the  paralysing  and  tetanising  action  of  curare  to 

H.  M.  Stanley  in  Central  Africa  is  compounded  from  five  plants.  Its  toxic 
action  is  believed  by  E.  M.  Hoi m e s  to  be  due  toerythrophlceine  and 
strychnine  (PAarm.  Jour.,  [31,  xxi.  917). 

1  See  a  valuable  paper  by  J.  Moss,  PJmrm.  Jour.,  [3],  viii.  121. 


CURARINE.  389 

curarine,  but  it  seems  not  improbable  that  the  preparation  contains 
at  least  two  active  alkaloids,  one  having  a  paralysing  and  the  other 
a  tetanising  action  (as  is  the  case  with  Calabar  bean).^ 

Curare  has  been  proposed  as  a  remedy  for  hydrophobia  and  as 
an  antidote  to  poisoning  by  strychnine. 

Curarine  is  the  name  given  to  the  physiologically  active  base  of 
curare,  and  the  improbable  formula  CjgHggN  has  been  ascribed  to 
it.  Curarine  has  been  variously  described  by  different  observers. 
and  it  appears  certain  that  the  products  have  been  of  very  discordant 
characters.  Curarine  is  described  (1865)  by  Preyer  (Ohem. 
News,  xii.  10)  as  crystallising  in  very  hygroscopic  four-sided  prisms, 
having  a  bitter  taste,  freely  soluble  in  water  and  alcohol,  only 
slightly  so  in  chloroform  and  amylic  alcohol,  and  insoluble  in  ethej-, 
benzene,  turpentine  and  carbon  disulphide. 

The  aqueous  and  alcoholic  solutions  of  curarine  have  a  bitter 
taste  and  faintly  alkaline  reaction.  The  base  is  said  to  form 
crystallisable  salts  with  hydrochloric,  nitric,  and  acetic  acids.^ 
The  commercial  curarine  prepared  by  Merck,  according  to  Bbhm's 
method,  is  described  as  a  yellowish  brown,  amorphous  powder  of 
intensely  bitter  taste,  easily  soluble  in  water  and  alcohol,  but 
insoluble  in  ether.  It  shows  no  perceptible  alkaline  reaction,  and 
forms  no  true  salts ;  but  on  evaporating  an  aqueous  solution  in 
dilute  acid  to  a  syrup,  acicular  crystals  of  an  inactive  decomposi- 
tion-product are  formed,  whereas  the  lethal  dose  for  guinea-pigs 
of  curarine  itself  is  stated  at  0'00035  gramme  per  kilogramme  of 
weight.  Concentrated  sulphuric  acid  dissolves  Merck's  curarine 
with  crimson  colour,  changed  to  bluish  by  potassium  bichromate. 

With  strong  nitric  acid  Preyer  found  curarine  to  give  a  purple 
coloration,  and  with  concentrated  sulphuric  acid  a  magnificent 
and  lasting  blue  colour.  C.  Bernard  found  the  colour  with 
sulphuric  acid  to  be  a  carmine-red. 

If  a  filtered  and  highly  concentrated  solution  of  curarine  be 
mixed  with  dilute  glycerin,  and  a  saturated  solution  of  potassium 
bichromate  added,  amorphous  curarine  chromate  is  precipitated. 
Even  after  solution  in  boiling  water  it  is  again  deposited  in  an 
amorphous  state,  a  fact  which  distinguishes  it  from  strychnine 
^  That  the  tetanising  action  of  curare  is  due  to  the  species  of  Strychnos 
employed  for  its  preparation,  and  not  to  picrotoxin  or  other  principles  derived 
from  the  various  plants  sometimes  used  in  conjunction  with  it,  is  proved  by 
the  fact  that  a  genuine  specimen  of  the  bark  of  Strychnos  toxifera  produced  the 
same  symptoms  (J.  T  i  11  i  e.  Jour.  Anat.  and  Physiol. ,  xxv.  42  ;  see  also 
Nikolski  and  Dogiel,  Year- Book  Pharm.,  1891,  page  198). 

^According  to  Sachs  {Annalen,  cxci.  254),  Preyer's  crystalline  curarina 
sulphate  consisted  of  impure  calcium  phosphate  (?)  with  mechanically  adhering 


390  CURARINE. 

chromate,  which  forms  well-defined  crystals.  Curarine  chromate 
is  more  soluble  in  water  than  is  strychnine  chromate,  and  is  never 
perfectly  precipitated  even  by  addition  of  glycerin  or  alcohol. 

If  the  precipitate  of  curarine  chromate  be  kept  for  some  time  it 
decomposes,  but  if  treated  without  delay  with  concentrated 
sulphuric  acid  it  developes  a  magnificent  blue  colour,  which  is 
often  violet  in  the  presence  of  impurities.  (Pelican  observed  a 
brilliant  red  coloration.)  The  reaction  simulates  that  obtained  in 
a  similar  manner  with  strychnine,  but  curarine  can  be  separated 
from  strychnine  by  rendering  the  cold  solution  alkaline  with 
ammonia,  and  then  filtering.  Strychnine  will  be  found  in  the 
precipitate,  whilst  the  curarine  will  remain  in  the  liquid,  owing  to 
its  solubility  in  water.  The  filtrate  may  be  agitated  with  chloroform 
or  benzene  to  remove  any  trace  of  strychnine,  the  aqueous  liquid 
concentrated  and  the  curarine  converted  into  chromate  and  tested 
further,  as  already  described. 

Curarine  is  very  unstable,  and  hence  its  solution  should  be 
subjected  to  as  little  manipulation  as  possible. 

CuRiNB  exists,  according  to  Bohm  {Ber.,  xx.  143),  together 
with  curarine  in  many  specimens  of  commercial  curare.  Curine  is 
said  to  exist  in  the  aqueous  extract  of  curare,  though  in  some  cases 
dilute  sulphuric  acid  is  requisite  for  its  complete  solution.  Upon 
rendering  the  liquid  slightly  alkaline  with  ammonia,  a  dirty 
green  precipitate  of  impure  curine  is  found,  which,  by  successive 
purifications  with  ether,  alcohol,  and  again  with  ether,  may  be 
obtained  in  a  micro-crystalline  condition.  Curine  is  described  as 
melting  at  160°  to  a  clear  liquid,  and  being  slightly  soluble  in  cold 
water,  freely  in  alcohol,  chloroform,  and  dilute  acids,  but  less 
readily  in  ether.  The  most  characteristic  reaction  of  curine  is  the 
formation  of  a  voluminous  white  precipitate  with  metaphosphoric 
acid.  Curine  itself  is  stated  by  Bbhm  to  be  physiologically  in- 
active (in  doses  of  5  to  10  milligrammes),  but  by  treating  it  with 
methyl  iodide  he  obtained  the  hydriodide  of  a  new  base  which 
possessed  an  intense  curare  action,  1  milligramme  killing  a  guinea- 
pig  (weighing  1600  grammes)  in  one  hour.  J.  T\\\\q  {Journ, 
Anat.  and  PhysioL,  xxv.  42)  states  that  curine  has  no  apparent 
action  on  motor  nerves,  but  when  hypodermically  injected  acts  on 
the  hearts  of  both  frogs  and  rabbits  as  a  paralysant  similar  ta 
veratrine  or  digitalis.  As  curine  is  liable  to  be  present  in  curare 
in  very  variable  proportions,  its  possible  presence  in  commercial 
curarine  must  not  be  overlooked. 


CINCHONA  BASES.  391 


CINCHONA  ALKALOIDS.^ 

The  various  species  of  the  family  of  plants  known  as  the 
Cinchonaceoe  yield  an  extraordinary  number  of  closely  analogous 
alkaloids.  These  bases  exist  chiefly,  though  not  wholly,  in  the 
bark  of  the  trees,  and  are  remarkable  for  their  valuable  febrifuge 
properties. 

The  constitution  of  the  cinchona  bases  is  at  present  very  imper- 
fectly understood.  Quinamine  and  cupreine  are  known  to  contain 
hydroxy  1-groups,  and  quinine  and  cinclionine  and  their  isomers 
have  been  proved  to  be  derivatives  of  quinoline.  An  abstract  of 
the  existing  knowledge  of  the  subject  is  given  on  page  168. 

Any  satisfactory  classification  of  the  cinchona  bases  in  the 
present  imperfect  state  of  our  knowledge  of  their  constitution,  and 
in  some  cases  even  of  their  empirical  formulae,  is  manifestly  impos- 
sible. Isomerism  is  common,  and  on  slight  provocation  quinine 
and  some  others  suffer  polymerisation,  with  or  without  losing  the 
elements  of  water,  forming  amorphous  "  apo-"  or  anhydro-bases. 

Perhaps  the  most  suggestive  method  of  classifying  the  cinchona 
bases  and  their  allies  is  to  arrange  them  according  to  the  number 
of  atoms  of  oxygen  in  the  molecule,  and  subdivide  these  classes 
according  to  other  analogies. 

The  following  (pages  392,  393)  is  a  tabular  list  of  the  alkaloids 
hitherto  isolated  from  the  various  species  of  cinchona  and  allied 
barks.  It  contains  the  names  of  all  the  natural  cinchona  bases, 
the  existence  of  which  as  chemical  individuals  has  been  fairly 
well  established  up  to  the  present  time;  but  it  must  not  be  sup- 
posed to  include  all  that  actually  exist. 

As  is  evident  from  the  table,  isomerism  is  very  common  among 
the  cinchona  bases.  Thus  the  two  best-known  bases  are  quimwe 
and  cinchomwe.  Isomerides  of  these  bases  coexist  with  them  in 
the  bark,  and  are  called  respectively  c^midine  and  cinGhomdine, 
It  is  probable,  however,  that  the  base  usually  termed  cinchonidine 
presents  the  closest  parallelism  with  quinine,  and  that  cinchonine 
is  the  analogue  of  quinidine. 

The  four  bases  above  mentioned  are  the  chief  crystallisable 
alkaloids  of  cinchona  barks,  but  there  exist  with  them,  or  are 
formed  in  the  process  of  manufacture,  certain  amorphous  isomerides 
called  respectively  qjimicine  and  cmchonicine.  It  is  doubtful  how 
far  these  bases  pre-exist  in  the  bark,  the  natural  amorphous  alka- 
loids   being    probably   the    anhydro-derivatives    diquinicine    and 

1  The  author  is  indebted  to  Dr  B.  H.  Paul  and  Mr  A.  J.  Cownley  for  the 
perusal  and  correction  of  this  section. 


392 


CINCHONA  ALKALOIDS. 


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CINCHONA   ALKALOIDS. 


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394  CINCHONA   ALKALOIDS. 

dicinchonicine,  and  distinct  from  the  amorphous  products  formed 
from  the  crystallisable  bases  by  the  action  of  heat  or  acids. 

In  addition  to  these  isomers  and  anhydro-derivatives  of  th& 
cinchona  bases,  there  exist  various  homologues  and  isologues  of 
them.  Quinine  itself  is  probably  a  methyl-cupreine  and  a 
methoxy-cinchonine. 

Certain  of  the  cinchona  bases  (e.g.,  cupreine)  exhibit  a 
remarkable  tendency  to  form  stable  crystalline  compounds  with 
other  of  the  bases.  It  is  probable  that  the  existence  of  these 
remarkable  compounds,  having  different  physical  properties  in  the 
form  of  salts  as  weU  as  in  the  free  state,  has  led  to  the  isolation 
and  description  of  various  bases  which  will  hereafter  be  found  to 
be  compounds. 

The  less  important  cinchona  bases  have  no  recognised  position 
in  commerce  or  medicine,  but  they  are  liable  to  be  present  to  a 
greater  or  less  extent  in  specimens  of  commercial  alkaloids  called 
by  the  better-known  names.  Commercial  quinine  is  liable  to 
retain  traces  of  cinchonine,  quinidine  and  hydroquinine,  and 
generally  contains  notable  proportions  of  cinchonidine.  Hydro- 
cinchonidine  is  sometimes  present  in  commercial  cinchonidine^ 
while  quinidine  contains  hydroquinidine  and  hydroquinine. 
Quinamine  and  conquinamine  are  probably  not  unfrequently  present 
in  commercial  cinchona  alkaloids. 

General  Properties  of  Cinchona  Bases. 

The  cinchona  alkaloids  all  have  well-defined  basic  characters, 
some  of  them  being  sufficiently  powerfill  to  displace  ammonia  from 
its  compounds.     Their  salts  are  usually  crystallisable. 

In  the  free  state,  the  cinchona  alkaloids  are  colourless  or  faintly- 
yellow  solids,  often  readily  fusible,  but  not  volatile  without 
decomposition.  They  have  generally  but  little  solubility  in  water, 
but  dissolve  more  readily  in  alcohol,  and  generally  with  great 
facility  in  ether  and  chloroform.  Such  as  are  soluble  in  the  last  two 
liquids  are  removed  from  their  ammoniacal  solutions  by  agitation 
with  ether  or  chloroform,  but  in  no  case  will  ether  or  chloroform 
remove  them  from  an  aqueous  solution  acidulated  with  sulphuric 
or  hydrochloric  acid.  On  the  other  hand,  the  anhydrous  sulphates 
of  many  of  the  cinchona  alkaloids  are  soluble  in  chloroform,  and 
still  more  readily  in  a  mixture  of  chloroform  and  absolute  alcohol. 
This  fact  is  sometimes  utilised  for  detecting  adulterations  (p.  417). 

The  solutions  of  some  of  the  cinchona  alkaloids  in  excess  of 
dilute  sulphuric  acid  exhibit  a  strong  blue  fluorescence,  which  is 
visible  even  in  very  dilute  liquids.  This  fluorescence  is  destroyed 
by  adding  an  excess  of  chloride  of  sodium  or  other  haloid  salt. 


CHARACTEKS   OF   CINCHONA   BASES.  395 

The  solutions  of  the  cinchona  alkaloids  exert  a  well-marked 
rotatory  action  on  polarised  light,  the  rotation  being  in  some  cases 
right-  and  in  others  left-handed.  The  specific  rotation  is  affected 
in  a  remarkable  manner  by  the  solvent  employed  and  by  the  pro- 
portion of  free  acid  present,  which  circumstances  greatly  reduce 
the  practical  value  of  the  optical  activity  for  the  identification  and 
quantitative  determination  of  the  unmixed  alkaloids. 

On  adding  a  fixed  alkali,  alkaline  carbonate  or  ammonia  to  the 
solution  of  a  salt  of  one  of  the  cinchona  bases,  the  sparingly  soluble 
alkaloid  is  usually  separated  in  a  free  state,  and  is  in  some  cases 
soluble  in  an  excess  of  the  precipitant.  On  agitating  the  alkaline 
liquid  with  chloroform,  the  precipitated  alkaloid  is  usually  dis- 
solved,^ and  may  be  recovered  in  a  free  state  by  separating  the 
chloroform,  and  evaporating  it  to  dryness  at  a  steam-heat.  By 
adding  more  chloroform  to  the  aqueous  liquid,  and  repeating  the 
agitation,  the  complete  extraction  of  the  alkaloid  may  be  ensured, 
and  the  process  made  quantitative  (see  page  419).  Ether  may  be 
substituted  for  chloroform  in  the  case  of  quinine  and  other 
alkaloids  readily  dissolved  by  it. 

The  cinchona  bases  are  tertiary  amines ;  for  when  treated  with 
an  alkyl  iodide  they  form  additive-compounds  which  are  converted 
by  treatment  with  oxide  of  silver  into  powerful  soluble  bases 
analogous  to  the  tetrethyl-ammonium  hydroxide  (page  19). 

Many  of  the  cinchona  alkaloids  form  two  series  of  salts ;  neutral 
(improperly  called  "  basic  "),  and  acid  salts.  The  neutral  sulphates 
of  the  cinchona  alkaloids  have,  when  anhydrous,  the  general  formula 
BgHgSO^.  They  have  a  neutral  reaction  to  litmus  and  methyl- 
orange,  and  are  generally  very  sparingly  soluble  in  water;  but  the 
corresponding  acid  or  bi-sulphates  (BH2SO4)  are  generally  readily 
soluble.     In  some  cases  still  more  acid  sulphates  are  known. 

The  sulphates  of  many  of  the  cinchona  bases  possess  the  property 
of  combining  with  iodine,  the  compounds  produced  being  in  some 
cases  of  a  very  complex  character.  Certain  of  tljese  *'io do- 
sulphate  s,"  of  which  the  quinine  compound  or  herepathite 
is  the  type,  possess  the  remarkable  optical  properties  of  the  tour- 
maline (see  page  403). 

When  a  salt  of  one  of  the  natural  cinchona  bases  is  heated  for 
a  prolonged  period  to  a  high  temperature,  the  alkaloid  undergoes  a 
curious  change.  It  becomes  incapable  of  crystallising,  a  property 
sometimes  extending  to  its  salts.  The  change  occurs  most  readily 
by  exposing  the  acid  sulphate  of  the  alkaloid  to  a  temperature  of 
100°  till   anhydrous,  and  then  increasing  the  heat  for  some  time 

^  This  is  not  the  case  with  cupreine  and  some  other  alkaloids,  which  form 
definite  compounds  with  the  fixed  alkalies  in  the  same  manner  as  morphine. 


396  REACTIONS  OF   CINCHONA  BASES. 

to  about  130"  C.  No  means  are  at  present  known  by  which  the 
modified  alkaloid  can  be  restored  to  its  original  crystallisable  con- 
dition. 

When  the  cinchona  bases  are  heated  with  strong  hydrochloric 
acid  (sp.  gr.  1'125)  to  150°  for  six  to  ten  hours,  they  are  converted 
into  apo-  or  anhydro-derivatives  of  basic  charact.er,  the  change  in 
the  case  of  quinine  and  quinidine  being  attended  with  evolution 
of  methyl  chloride  (Hesse,  Annal,  ccv.  314). 

When  the  sulphates  of  quinine,  cinchonine,  and  cinchonidine 
are  dissolved  in  concentrated  sulphuric  acid  at  the  ordinary  tem- 
perature, they  are  converted  into  "iso-bases"  (Hesse,  Annal., 
ccxliii.  131),  which  differ  in  several  respects  from  the  parent 
alkaloids.  Hydroquinine,  hydroquinidine,  and  hydrocinchonidine 
are  converted  by  the  same  treatment  into  the  corresponding  sul- 
phonic  acids,  which  are  compounds  of  distinct  basic  character. 

With  platinic  chloride,  the  hydrochlorides  of  the  cinchona  bases 
form  chloroplatinates  of  the  general  formula  BHgPtClg, 
but  many  of  them  also  form  salts  containing  B2H2PtClg.  Salts  of 
this  constitution  are  produced  on  adding  sodio-platinic  chloride  to 
neutral  solutions  of  quinine,  quinidine,  cinchonidine,  and  homo- 
<5inchonidine  (Hesse,  AnnxiL,  ccvii.  922).  The  auro-chlo- 
rides  of  the  cinchona  bases  are  mostly  unstable,  and  liable  to 
speedy  decomposition  with  separation  of  finely-divided  metallic  gold. 

Certain  of  the  cinchona  bases  give  a  deep  green  coloration  or 
precipitate  when  their  solutions  are  treated  with  chlorine  or 
bromine  water,  and  ammonia  subsequently  added.  This  reaction 
is  known  as  the  "thalleioquin   test"  (see  also  page  401). 

Most  of  the  cinchona  bases  are  very  completely  precipitated  by 
tannic  and  picric  acids,  potassio-mercuric  iodide,  and  certain  other 
reagents.  These  reactions  are  sometimes  used  for  their  detection 
and  separation. 

On  treatment  in  solution  with  bromine-water  in  slight  excess, 
the  cinchona  bases  are  converted  into  bro  mo-derivatives. 
The  number  of  atoms  of  bromine  taken  up  varies  with  the  con- 
stitution of  the  alkaloid.  According  to  T.  Fawssett  (Pharm. 
Jour.,  [3],  xix.  915),  quinine,  quinidine,  and  cupreine  react  with 
approximately  Brg,  hydroquinine  with  Br^,  and  cinchonine,  cinchoni- 
dine, and  "  amorphous  quinine"  with  Brg.  On  heating  the  cinchona 
bases,  or  their  hydrochlorides  or  sulphates,  with  acetic  anhydride 
to  about  80°  0.  for  a  few  hours,  they  are  converted  into  acetyl- 
derivatives  (Wright  and  Beckett,  Jour.  Chem.  Soc, 
xxix.  655  ;  0.  H  e  s  s  e  ,  Annal,  ccv.  314).  With  the  exception  of 
the  acetyl-derivative  of  quinine,  all  these  compounds  are  amorphous. 
They  can  be  dried  at   100°  without  change,  are   readily  soluble  in 


REACTIONS   OF   CINCHONA   BASES.  397 

dilute  acids,  and  are  thrown  down  as  resinous  precipitates  by 
alkalies.  On  treatment  with  alcoholic  potash  they  are  hydrolysed 
into  acetic  acid  and  the  original  bases.  The  acetyl-derivatives  of 
quinine  and  quinidine  give  the  thalleioquin  reaction. 

The  more  important  properties  of  the  leading  cinchona  alkaloids 
may  be  summarised  as  follows  : — 

(Hydrated  crystals  are  formed  by  Quinine,   Quinidine,  Paytine,  Cupi-eine, 
Cusconine,  Chairamine. 
Anhydi'OiLs  crystals  are  formed  by  Cinchonine,  Cinohonidine,  Quinamine. 
No  crystals  are  formed  hy  Paricine,  Quinicine,  Diquinicine,  Dicinchonicine. 
f  Readily  soluble  in  Ether : — Quinine,  Quinamine,  Paytine,  Quinicine,  Java- 
nine. 
Sparingly  soluble  in  Ether : — Cinchonidine,  Quinidine,  Cupreine. 
Almost  insoluble  in  Ether : — Cinchonine. 

'Dextro-rotatory  solutions  in  alcohol  are  formed  by  Cinchonine,  Cinchon- 
amine,    Quinamine,    Quinidine,    Chairamine,    Quinicine,    Diquini- 
cine. 
Lcevo-rotatory  solutions  in  alcohol  are  formed  by  Cinchonidine,  Hydro- 
cinchonidine,     Homocinchonidine,     Paytine,     Cupreine,      Quinine, 
Hydroquinine,  Cusconine,  Aricine. 
[Fluorescent  solutions  in  dilute   sulphuric  acid  are   formed   by  Quinine, 
Quinidine,  Hydroquinine,  Hydroquinidine,  Diquinicine. 
D-(  No  fluorescence  is  exliibited  by  solutions  of  Cinchonine,   Cinchonidine, 
Hydrocinchonidine,  Homocinchonidine,  Quinamine,  Quinicine,  Dicin- 
chonicine, Cusconine,  Cupreine. 

'Thalleioquin  is  formed  by  Quinine,  Quinidine,   Quinicine,  Diquinicine, 
Hydroquinine,  Hydroquinidine,  Cupreine. 
Thalleioquin  is  not  formed  by  Apoquinidine,  Cinchonine,   Cinchonidine, 
Homocinchonidine,    Hydrocinchonidine,    Cinchonicine,   Dicinchoni- 
cine, Quinamine,  Cinchonamine. 

Quinine.     Quinia. 

C20H24N2O2;  or  C9H6(O.CH3)N.C9Hii(OH)KCH3. 

Quinine  is  the  most  important  of  the  cinchona  bases,  and  appears 
to  possess  the  most  powerfully  febrifuge  properties.  Its  mode  of 
preparation  from  the  bark  is  based  on  the  same  principles  as  its 
determination  in  the  same.-^ 

^  The  finely-powdered  bark  is  ground  to  a  thin  paste  with  lime,  caustic  soda, 
or  sodium  carbonate,  and  extracted  with  warm  paraffin  oil.  On  standing  the 
oil  separates,  when  it  is  run  off  and  shaken  with  sulphuric  acid  ;  this  solution 
is  boiled,  and  whilst  boiling  is  neutralised  with  sodium  carbonate  and  allowed 
to  cool.  Quinine  sulphate  crystallises  out  on  cooling,  whilst  cinchonidine, 
cinchonine,  and  quinidine  remain  in  solution  as  sulphates.  The  quinine  sul- 
phate is  purified  by  recrystallisation  after  treatment  with  animal  charcoal. 
The  mother-liquor  containing  the  other  alkaloids  is  treated  with  caustic  soda. 


398  CHARACTERS   OF   QUININE. 

The  chemical  constitution  of  quinine  is  not  thoroughly  under- 
stood, but  such  knowledge  as  exists  is  epitomised  on  page  168. 
The  complete  synthesis  of  the  alkaloid  has  not  hitherto  been 
effected,  but  cupreine  has  been  apparently  converted  into  quinine 
by  the  introduction  of  a  methyl-group.^  Two  distinct  bodies 
isomeric  with  quinine  have  been  synthetically  prepared  (page 
169). 

Free  quinine  usually  appears  as  an  amorphous  or  resinous  mass. 
In  commerce  the  free  alkaloid  is  usually  met  with  as  a  coarse 
powder,  having  a  brownish  yellow  tint  owing  to  a  trace  of  colour- 
ing-matter.    It  may  also  be  obtained  as  a  fine  white  powder. 

From  alcohol  and  some  other  solvents  quinine  may  be  obtained 
in  crystals,  but  on  the  evaporation  of  its  ethereal  solution  it 
separates  as  a  gelatinous  or  resinoid  mass,  which  is  never  crystal- 
line. This  behaviour  is  important,  as  most  other  cinchona  bases 
give  crystalline  ether-residues. 

As  obtained  by  the  precipitation  of  one  of  its  salts  by  an 
alkali,  quinine  forms  a  bulky,  white  precipitate,  which  coagu- 
lates into  a  resinoid  mass  by  very  slight  elevation  in  temperature. 
According  to  Q.  H  e  s  s  e  the  precipitate  at  first  formed  at  the 
ordinary  temperature  is  amorphous  and  anhydrous,  but  it  soon 
takes  up  water  and  becomes  crystalline.  It  then  contains  3  aqua. 
If  the  ammonia  be  added  in  large  excess,  and  the  solution  is  not 
too  concentrated,  the  trihydrate  is  obtained  in  small  needles, 

and  extracted  with  weak  alcohol.  Of  the  three  bases  precipitated  by  the 
alkali,  quinidine  and  cinchonidine  are  dissolved  by  the  spirit,  whilst  cinchonine 
is  left  behind  ;  the  two  former  can  then  be  separated  by  means  of  their  neutral 
tartrates,  that  of  quinidine  being  considerably  the  more  soluble. 

Chemically  pure  quinine  is  manufactured  by  preparing  the  acid  sulphate, 
which  after  undergoing  sufficient  purification  is  reconverted  into  the  neutral 
salt.  The  consumption  of  quinine  amounts  to  200,000  kilos,  annually.  The 
Ceylon  bark  yields  about  2-4  per  cent,  of  quinine  sulphate  ;  Java  bark,  4  to  9 
per  cent.,  and  even  up  to  13  per  cent.  The  more  recent  cultivations  of  cinchona 
bark  in  Peru  and  Bolivia  are  of  special  importance  ;  such  bark  yields  about 
4  to  5  per  cent,  of  sulphate  of  quinine. —CAew.  Zeit,  xv.  735. 

iQrimaux  and  Arnold,  Oompt.  Rend.,  cxii.  774.  When  a  solution  of 
cupreine  in  methyl  alcohol  is  boiled  for  several  hours  under  an  upright  con- 
denser, with  the  theoretical  quantity  of  sodium  and  excess  of  methyl  iodide,  a 
mixture  of  two  iodomethylates  was  obtained,  having  all  the  characteis  of  the 
compounds  resulting  from  the  similar  treatment  of  quinine.  By  substituting 
methyl  chloride  for  the  iodide,  and  operating  in  a  sealed  tube  at  1 00°,  a  base 
was  formed,  the  sulphate  of  which  had  all  the  chemical  and  physical  characters 
of  quinine  sulphate,  the  following  reaction  having  probably  occurred  : — 

Ci9N2,N.,0.  ONa  +  CH3CI  =  NaCl  +  CisHoiN^O.  OCH3 . 
Sodium  compound  Quinine, 

of  cupreiue. 


HYDRATES   OF   QUININE.  399 

and  the  same  compound  can  be  obtained  from  an  ethereal  solution 
below  10°.  But  the  resinoid  mass  left  on  the  spontaneous  evapora- 
tion of  a  solution  of  quinine  in  ether  usually  contains  water  in 
proportion  corresponding  to  a  m  o  n  o  h  y  d  r  a  t  e,  and  when  the 
crystallised  trihydrate  is  exposed  in  an  exsiccator  over  sulphuric 
acid,  it  effloresces  and  loses  its  water  more  or  less  perfectly.  At 
20°  C,  over  strong  sulphuric  acid,  the  trihydrate  soon  loses  the 
whole  of  its  water,  but  over  equal  measures  of  strong  sulphuric 
acid  and  water  a  monohydrate  results.  At  15°  C,  in  the  open 
air,  the  trihydrate  is  unaltered,  but  at  20°  C.  it  effloresces  and 
loses  1  aqua,  the  residue  having  the  composition  of  a  dihydrate. 
Commercial  quinine  contains  from  8  to  11  per  cent,  of  water,  and 
hence  is  approximately  a  dihydrate.  The  precipitate  produced  by 
ammonia  at  a  low  temperature  in  concentrated  solutions  of  quinine 
sulphate  is  also  usually  a  dihydrate.  Hydrates  of  quinine  con- 
taining 8  and  9  aqua  have  also  been  described.  When  the  tri- 
hydrate is  exposed  to  a  temperature  of  40°  for  a  short  time,  and 
then  to  60°,  the  whole  of  the  water  is  driven  off,  and  this  change 
occurs  rapidly  at  100°.  Resinoid  quinine  loses  its  water  with 
some  difficulty  at  100°  unless  previously  powdered,  but  at  120° 
becomes  anhydrous  very  rapidly  (see  Fharm.  Jour.^  [3],  xvi.  386, 
897,  937). 

Anhydrous  quinine,  obtained  by  drying  the  trihydrate  over 
sulphuric  acid  and  heating  to  115°-120°,  melts  at  171-2°-172°, 
and  that  prepared  by  heating  the  benzene  compound  to  120°  at 
171'6°-172°.i 

Quinine  is  odourless.  When  in  solution  or  finely-divided  it 
has  an  intense  and  purely  bitter  taste.  It  has  valuable  febrifuge 
properties,  and  is  poisonous  to  frogs  and  other  of  the  lower 
animals.  It  has  decided  antiseptic  properties,  retarding  or  arrest- 
ing the  alcoholic,  lactic,  butyric,  amygdalous,  and  salicylous  fer- 
mentations, but  not  the  digestive  action  of  pepsin. 

Quinine  is  very  sparingly  soluble  in  water,  according  to  J. 
Regnauld  the  solubility  at  15°  C.  being  1  part  in  2024. 
According  to  S  e  s  t  i  n  i,  however,  the  solubility  of  the  anhydrous 
alkaloid  in  water  is  1  in  1667  at  20°  and  1  in  902  at  100°  C, 
the  trihydrate  requiring  1428  and  773  parts  of  water  at  the  same 
temperatures. 

In  dilute  solutions  of  the  fixed  alkalies  quinine  is  not  more 

^  According  to  H  e  s  s  e  {Annal.,  cclviii.  133)  on  prolonged  heating  of  a  solu- 
»ion  of  quinine  in  alcohol  to  30°  the  alkaloid  is  converted  into  an  isomeride 
for  which  he  proposes  the  unsuitable  name  of  homoquinine.  This  melts 
at  174'4''-175°,  and  is  reconverted  into  quinine  by  prolonged  heating  with  dilute 
sulphuric  acid. 


400  PROPERTIES   OF   QUININE. 

soluble  than  in  pure  water,  but  ammonia  exercises  considerably 
greater  solvent  action.  Certain  ammonium  and  calcium  salts 
notably  increase  the  solubility  of  quinine  in  aqueous  liquids. 

Quinine  dissolves  in  about  two  parts  of  alcohol  of  0'82  sp.  gr., 
and  is  still  more  soluble  in  boiling  alcohol.  Crystallised  quinine 
is  stated  to  require  from  22  to  30  parts  of  ether  for  solution,  but 
freshly-precipitated  quinine  dissolves  in  little  more  than  its  own 
weight  of  ether.  Quinine  is  also  very  soluble  in  chloroform 
(1  :  5),  and  dissolves  readily  in  benzene^  and  carbon  disulphide- 
It  is  only  sparingly  soluble  in  petroleum  spirit,  even  when  hot. 

Quinine  exercises  a  powerful  IsBvo-rotatory  action  on  polarised 
light,  the  value  of  Sp  being,  according  to  Hesse -145'2° 
—  0-657  c  at  15°  C,  for  the  solution  of  the  hydrated  alkaloid  in 
97  per  cent,  alcohol.  In  its  salts,  the  optical  activity  of  quinine 
has  different  values. 

Quinine  affords  no  visible  colour  or  other  reactions  with  strong 
acids.  By  cautiously  dissolving  quinine  hydrate  or  sulphate  in  a 
mixture  of  equal  volumes  of  concentrated  nitric  and  sulphuric 
acids,  amorphous  dinitroquinine,  C2oH22(N02)2N'202,  is  pro- 
duced, nearly  insoluble  in  ether  and  forming  uncrystallisable 
salts  (E.  H.  R  e  n  n  i  e,  Jour.  Chem.  Soc,  xxxix.  469).  The  action 
of  permanganate  and  chromic  acid  mixture  on  quinine  is  described 
on  page  168. 

Quinine  is  a  powerful  base,  its  solutions  having  a  marked 
alkaline  reaction  to  litmus  and  methyl-orange,  and  neutralising  the 
strongest  acids.      It  does  not  redden  phenolphthalein. 

Detection  and  Determination  of  Quinine. 

The  detection  and  estimation  of  quinine,  when  it  occurs  unmixed 
with  other  alkaloids  or  organic  matter,  is  very  readily  effected,  but 
the  problem  becomes  more  complex  in  the  presence  of  other 
cinchona  bases. 

The  following  reactions  are  yielded  by  a  solution  of  quinine  in 
a  moderate  excess  of  dilute  sulphuric  acid  : — 

1.  Solutions  of  quinine  in  dilute  sulphuric  acid  exhibit  a 
strong  blue  fluorescence.  The  effect  is  best  observed  in  very 
dilute  liquids,  and  is  intensified  by  addition  of  excess  of  sulphuric 
acid.  The  hydrochloride  and  other  haloid  compounds  of  quinine 
(including  the  thiosulphate  and  cyanogen  compounds)  exhibit  no 
fluorescence  till  excess  of  sulphuric  acid  is  added,  and  the  fluores- 
cence of  solutions  of  the  sulphate  is  destroyed  by  very  small 
quantities  of  hydrochloric  acid  or  other  chlorides,  but  can  be  again 
produced  by  adding  excess  of   dilute  sulphuric    acid.     Alcoholic 

^  Quinine  is  deposited  from  its  solution  in  warm  benzene  in  crystals  contain- 
ing (C2oH24^202)2iC6H6,2aq.  {Cfliem.  News,  xlviii.  4). 


THALLEIOQUIN   REACTION.  401 

solutions  of  quinine  exhibit  but  little  fluorescence,  and  solutions  in 
the  alkaloid  in  immiscible  solvents  none  at  all.  Under  favourable 
conditions,  the  fluorescence  of  quinine  becomes  an  extremely 
delicate  test  for  the  presence  of  the  alkaloid.-^  Fluorescence  is 
also  produced  by  quinidine,  hydroquinine  and  hydroquinidine, 
and  diquinicine,  but  not  by  quinamine,  cinchonine  or  its  isomers, 
cusconine,  cupreine,  or  quinicine. 

2.  According  to  A.  Weller  (Arch.  d.  PJiarm.,  ccxxiv.  161), 
on  adding  chlorine-water  to  a  strong  solution  of  quinine  the  solu- 
tion acquires  a  more  or  less  intense  red  colour.  Bromine-water 
is  a  preferable  reagent,  and  on  adding  a  few  drops  to  a  saturated 
solution  of  quinine  hydrochloride  a  yellow  precipitate  is  formed, 
which  gradually  disappears  with  formation  of  a  rose-red  coloration, 
changing  to  cherry-red.  The  colour  disappears  after  a  time,  but 
can  be  reproduced  by  adding  more  bromine-water,  and  the  reaction 
is  more  delicate  and  prompt  if  the  quinine  solution  be  previously 
gently  warmed.  Acids  and  excess  of  bromine-water  prevent  the 
reaction,  which  is  also  produced  by  quinidine,  but  not  by 
cinchonine  or  cinchonidine. 

3.  If  a  solution  of  quinine,  rendered  as  nearly  neutral  as 
possible,  be  treated  first  with  chlorine  or  bromine,  and  then  with 
excess  of  ammonia,  a  green  substance  called  thalleioquin  is 
produced,  which  in  concentrated  solutions  forms  a  precipitate,  and 
in  more  dilute  a  deep  green  liquid.  When  carefully  applied,  the 
test,  which  is  due  to  B  r  a  n  d  e,  is  extremely  delicate.  Bromine 
is  a  more  sensitive  reagent  than  chlorine.  The  following  is  the 
best  mode  of  applying  the  test : — To  10  c.c.  of  the  solution  of 
quinine  add  3  c.c.  of  chlorine-water,  or  0'5  c.c.  of  saturated 
bromine-water.  Agitate  well,  and  then  add  one  drop  of  strong 
ammonia  solution,  or  sufficient  to  render  the  liquid  distinctly 
alkaline.  If  the  proportion  of  quinine  exceed  about  1  per  1000 
of  solution,  a  green  substance  is  precipitated,  soluble  in  absolute 

^  Tlie  fluorescence  of  quinine  is  best  observed  by  holding  a  test-tube  filled 
with  the  solution  in  a  vertical  position  before  a  window,  when  a  bluish 
"bloom  "  will  be  perceived  on  observing  the  liquid  from  above  against  a  dark 
background.  Another  plan  is  to  make  a  thick  streak  of  the  solution  on  a 
piece  of  polished  jet  or  black  marble,  or  on  a  plate  of  glass  smoked  at  the 
back,  and  to  place  the  streaked  surface  in  front  of,  and  at  right  angles  to,  a 
well-lighted  window. 

The  fluorescence  of  quinine  solutions  is  not  perceptible  by  gas-light,  but 
may  be  brought  out  by  burning  a  piece  of  magnesium  ribbon  in  the  proper 
position.  The  use  of  blue  glass,  which  transmits  the  ultra-violet  rays  which 
produce  the  fluorescence  of  quinine,  while  excluding  the  less  refrangible  rays, 
is  sometimes  recommended.  In  this  case  the  light  transmitted  by  the  glass 
should  be  concentrated  by  means  of  a  lens. 

VOL.  III.  PART  II.  2  C 


402  KEACTIONS  OF  QUININE. 

alcohol,  but  insoluble  in  ether  or  chloroform.  In  more  dilute 
liquids,  even  if  the  proportion  of  quinine  does  not  exceed  1  in 
20,000,  a  deep  green  coloration  is  produced.  If  the  green  am- 
moniacal  solution  be  just  neutralised  with  acid,  a  blue  coloration  is 
obtained,  and  on  adding  more  acid  a  colour  ranging  from  violet  to 
red,  but  changing  to  green  again  on  adding  excess  of  ammonia. 

H.  Trimble  has  proposed  to  use  this  reaction  for  the  approxi- 
mate colorimetric  determination  of  quinine.  He  dissolves  0*01 
gramme  of  a  quinine  salt  in  5  c.c.  of  fresh  chlorine-water,  and 
adds  10  c.c.  of  ammonia  solution.  The  sample  is  treated  in  the 
same  way,  and  the  proportion  of  quinine  ascertained  from  the 
relative  volumes  of  the  liquids  when  coloured  equally  intensely. 

The  thalleioquin  reaction  is  also  given  by  quinidine,  cupreine, 
hydroquinine,  hydroquinidine  and  diquinicine,  but  not  byquinamine, 
or  cinch onine  and  its  isomers.     It  is  prevented  by  morphine. 

4.  If,  after  the  addition  of  chlorine  or  bromine  water,  the 
quinine  solution  be  treated  with  a  few  drops  of  solution  of  potas- 
sium ferro-  or  ferri-cyanide,  ammonia  being  subsequently  added,  a 
red  coloration  is  produced  instead  of  a  green.  The  reaction  is  not 
so  delicate  as  the  thalleioquin  test,  but  affords  useful  confirmatory 
evidence  of  the  presence  of  quinine.  A.  V  o  g  e  1  modifies  the  test 
by  adding  bromine- water  and  potassium  ferrocyanide  to  the  solu- 
tion to  be  tested,  and  then  shaking  with  a  fragment  of  marble, 
which,  in  presence  of  quinine,  is  at  once  covered  with  a  red  film. 
Strychnine,  cinchonine,  and  caffeine  do  not  give  similar  reactions. 

5.  On  adding  a  fixed  alkali,  alkaline  carbonate,  or  ammonia  to 
a  solution  of  a  salt  of  quinine,  a  bulky  white  precipitate  of  the 
free  alkaloid  (more  or  less  hydrated)  is  produced.  The  precipitate 
is  very  sparingly  soluble  in  cold  water  or  excess  of  these 
precipitants,  with  the  exception  of  ammonia.  The  precipitate 
cannot  be  conveniently  filtered  off,  washed,  and  weighed,  as  it  is 
not  wholly  insoluble,  and  melts  with  very  slight  increase  of  tem- 
perature. Its  state  of  hydration  is  also  very  uncertain.  But,  if 
the  liquid  containing  the  precipitated  alkaloid  be  agitated  with 
ether  or  chloroform,  or  a  mixture  of  the  two,  the  quinine  passes 
readily  and  completely  into  solution,  and  may  be  obtained  in  the 
solid  state  by  evaporating  the  solvent.  The  process  is  readily 
made  quantitative  by  operating  with  care  and  repeating  the  agita- 
tion with  the  solvent,  and  the  quinine  may  be  weighed  in  the 
anhydrous  state  as  C20H24N2O2,  after  being  dried  at  100°  C.  till 
constant  in  weight ;  or  after  exposure  for  fifteen  or  twenty  minutes 
to  a  temperature  of  120°  C.  The  determination  of  quinine  in  this 
manner  is  capable  of  yielding  very  accurate  results,  and  is  of  very 
extensive  and  rapid  application. 


TITRATIONS  OF  QUININE.  403 

6.  When  quinine  exists  in  a  free  state,  as  it  is  obtained  in 
process  5  by  the  evaporation  of  its  solution  in  ether  or  chloroform, 
it  may  be  determined  by  titration  with  standard  acid.  Each  1  c.c. 
of  decinormal  sulphuric  acid  ( =  4'9  grammes  of  HgSO^  per  litre) 
corresponds  to  '0324  gramme  of  anhydrous  quinine.  The  process 
is  conducted  by  dissolving  the  ether-residue  in  hot  alcohol,  adding 
as  much  water  as  can  be  used  without  causing  precipitation,  and 
titrating  with  decinormal  acid.  The  indicator  may  be  litmus,  but 
methyl-orange  or  cochineal  is  decidedly  preferable.  Sharp  readings 
are  obtainable,  but  extreme  care  is  necessary,  owing  to  the  very 
high  combining- weight  of  quinine  (C2oH24N202=  324).  When 
methyl-orange  is  employed,  the  alkaloid  may  be  conveniently  used 
in  ethereal  solution,  and  in  this  case  previous  evaporation,  as 
described  under  5,  is  unnecessary,  provided  the  ethereal  solution 
be  washed  with  water  till  the  aqueous  liquid  gives  no  pink  colora- 
tion with  phenolphthalein.^  The  titration  by  standard  acid,  of 
course,  merely  indicates  the  total  alkaloid  present,  in  terms  of 
quinine.  The  process  furnishes  a  very  useful  check  on  the  deter- 
mination from  the  weight  of  the  chloroform  or  ether-residue,  and 
brings  the  alkaloid  into  a  convenient  form  for  further  examination 
by  one  of  the  following  processes  : — 

7.  On  adding  tincture  of  iodine  to  a  solution  of  acid  sulphate  of 
quinine  in  dilute  alcohol,  a  curious  compound  is  produced,  called, 
after  its  discoverer,  Herepathite,  and  having  the  formula 
4C2oH24N202,3H2S04,2HI,I^4-3aq.2  This  body,  called  also  the 
iodo-sulpha  te  of  quinine  or  sulphate  of  iodo- 
quinine,  is  the  type  of  a  series  of  similar  bodies  formed  by  the 
action  of  iodine  on  the  sulphates  of  the  cinchona  bases.  Here- 
pathite is  but  little  soluble  in  cold  water  or  dilute  alcohol,  and 
requires  1000  parts  of  hot  water  for  solution;  but  it  dissolves  in 
boiling  rectified  spirit,  and  is  deposited  on  cooling  in  tabular 
crystals,  remarkable  for  their  dichroism  and  their  action  on  light, 

^  As  quinine  has  no  action  on  plienolplithalein,  by  the  combined  use  of  this 
indicator  and  methyl-orange  it  maybe  determined  in  its  salts.  Standard  xu 
baryta-water  is  added  to  the  aqueous  liquid  until  the  change  of  the  liquid  to 
yellow  or  brown  shows  that  the  free  acid  is  neutrab'sed.  More  baryta  is  then 
added  slowly,  with  constant  stirring,  till  the  production  of  a  pink  colour  shows 
that  the  whole  of  the  acid  in  combination  with  the  alkaloid  is  neutralised. 
Each  1  c.c.  of  additional  ^n  alkali  required  represents  0-0162  gramme  of 
quinine.  Tlie  process  has  been  used  by  S  e  a  t  o  n  and  Richmond  for  deter- 
mining quinine  in  medicines  (Analyst,  xv.  43). 

2  Herepathite  may  be  readily  prepared  by  dissolving  the  sulphate  of  quinine 
in  10  parts  of  proof  spirit  containing  5  per  cent,  of  sulphuric  acid,  and  adding 
an  alcoholic  solution  of  iodine  as  long  as  a  black  precipitate  is  produced.  The 
preciiiitate  is  filtered  off,  washed,  and  recrystallised  from  hot  alcohol. 


404 


HEREPATHITE. 


a  thill  film  of  herepathite  polarising  the  transmitted  light  as 
completely  as  the  tourmaline.  Herepathite  is  re-converted  into 
sulphate  of  quinine  by  treatment  with  sulphurous  acid,  thio- 
sulphates,  sulphuretted  hydrogen,  and  other  reducing  agents. 

lodosulphate  of  quinine  possesses  far  less  solubility  than  the 
corresponding  compounds  of  the  other  cinchona  bases.^  This  fact 
has  been  utilised  by  J.  E.  de  Vrij  for  the  determination  of 
quinine  (PJiarm.  Jour.,  [3],  vi.  461). 

With  the  pure  alkaloid  the  method  is  capable  of  yielding 
tolerably  accurate  results  if  a  correction  for  solubility  be  applied, 
but  investigations  by  A.  Christensen,  B.  Y.  Shimoyama 
and  others  have  shown  the  process  to  have  a  limited  practical  value, 
as  it  is  seriously  invalidated  by  the  presence  of  cinchonidine  (Pharm. 
Jour.,  [3],  xii.  441,  1016;  xvi.  205;  xvii.  654).  De  Yrij's 
most  recent  method  of  operating  is  described  on  page  456. 

E.  B.  Stuart  (P/iarw.  Jour.,  [3],  xii.  1016)  finds  the  here- 
pathite reaction  equally  delicate  with  the  thalleioquin  test,  and  quite 
as  easy  of  application.  The  salt  of  quinine  should  be  dissolved  in 
dilute  alcohol,  and  dilute  sulphuric  acid,  the  presence  of  which  is 
essential,  added.  Very  dilute  tincture  of  iodine  is  then  added, 
drop  by  drop,  with  constant  agitation,  when  the  precipitate  suddenly 

^  B.  Y.  Shimoyama  {Tlmrm.  Jour.,  [3],  xvi.  205)  gives  the  following 
figures  for  the  solubility  of  quinine  herepathite  in  90  per  cent,  alcohol  at 
diflferent  temperatures : — 


Temperature ;  "C. 

Alcohol  without  Acid. 

Acidulated  Alcohol. 

15 

1  in  869  parts. 

1  in  255  parts. 

16 

.,    841     „ 

... 

17 

... 

1  in  117  parts. 

18 

„    101     „ 

20 

1  in  733  parts. 

... 

25 

„    660     „ 

... 

90 

,.     638     „ 

... 

The  solubilities  of  the  iodosulphates  of  the  principal  cinchona  alkaloids  in 
acidulated  alcohol  at  15°  C.  were  found  to  be  as  follow  : — 


Alkaloid. 

Solubility. 

Percentage  of  Iodine. 

Quinine  herepathite,  . 
Cinchonidine,      . 
Quinidine,   . 
Cinchouine, 

1  in  255  parts. 
.,      92     „ 
»      61      „ 
>,      42     „ 

32-37 
53-68 
42-70 
24-90 

QUININE   CHROMATE.  405 

appears  and  quickly  subsides.  Precipitation  as  herepathite  may 
be  used  with  advantage  for  separating  quinine  from  morphine 
even  when  the  relative  proportions  are  as  1  :  1000. 

8.  In  1862,  Andr^  {Jour,  de  Pharm.,  xli.  341)  described  a 
method  of  estimating  quinine  and  separating  it  from  other  cin- 
chona bases  by  precipitation  as  the  chromate,  which  is  stated 
to  be  soluble  in  160  parts  of  boiling  water  or  2400  of  water  at 
15°  C,  and  not  liable  to  alteration  by  light  or  on  boiling  an 
aqueous  solution.  A  method  of  assaying  quinine,  based  on  the 
same  principle,  was  described  in  1887  by  J.  E.  de  Yrij  {Arch. 
Pharm.,  [3],  xxiv.  1073),  who  attributes  to  the  precipitate  the 
formula  (C2oH24N202)2H2Cr04,  and  states  that  it  is  soluble  in  2733 
parts  of  water  at  12°,  or  2000  parts  at  16°  C.  He  directs  that  5 
grammes  of  quinine  sulphate  should  be  dissolved  in  500  c.c.  of  hot 
water,  and  a  solution  of  1'2  gramme  of  neutral  potassium  chromate 
in  a  little  warm  water  added.  After  standing  in  the  cold  for 
twelve  hours,  the  precipitate  is  filtered  off,  washed  with  cold  water, 
and  weighed  after  drying  in  the  air.  A  correction  of  0  005  gramme 
is  made  for  every  10  c.c.  of  mother-liquor  and  wash  water.  This 
method  has  been  severely  criticised  by  0.  Hesse  (Pharm.  Jour.j 
[3],  xvii.  585,  665;  xviii.  582),  who  finds  the  precipitated 
chromate  of  quinine  to  contain  2  aqua,  which  fact  accounts  for 
some  experimenters,  working  according  to  de  Yrij's  directions, 
having  obtained  an  apparent  excess  of  quinine.  On  the  other 
hand,  cinchonidine  and  hydroquinine  are  in  part  thrown  down 
with  the  quinine,  which  renders  the  method  inapplicable  for 
separating  quinine  from  its  most  constant  associates. 

Quinine  is  distinguished  : — 

1.  From  cinch  on  in  e,  a,  by  its  fluorescence;  b,  its  Isevo- 
rotation ;  c,  the  thalleioquin  test ;  d,  the  crystallisation  of  the 
sulphate ;  e,  its  solubility  in  ether ;  /,  its  solubility  in  ammonia ; 
g,  the  sparing  solubility  of  the  iodosulphate. 

2.  From  cinchonidine  by  most  of  the  above  reactions, 
except  b,  and  less  sharply  than  cinchonine  by  those  tests  depending 
on  relative  solubility  (d,  e,  f,  g). 

3.  From  quinidine  by  &,  c?,  /,  g ;  also  by  (Ji)  yielding  no 
precipitate  with  potassium  iodide,  and  (z)  the  insolubility  of  the 
sulphate  in  chloroform. 

4.  From  q  u  i  n  a  m  i  n  e  by  b,  e;  j,  precipitation  as  tartrate ; 
and  k^  the  sparing  solubility  of  the  sulphate. 

5.  From  cupreine  by  a,  and  (I)  the  insolubility  of  the 
precipitated  alkaloid  in  excess  of  soda. 

Methods  for  the  separation  of  quinine  from  the  associated 
cinchona  bases  are  given  on  pages  411,  453,  et  seq.  '■ 


406  QUININE   SULPHATE. 

The  separation  of  quinine  from  morphine  may  be  effected,  as 
already  stated  (page  405),  by  precipitation  as  herepathite ;  also 
by  treating  the  free  alkaloids  with  chloroform  or  ether,  which 
leaves  the  morphine  undissolved. 

From  strychnine,  quinine  may  be  separated  as  indicated  under 
"Easton's  syrup"  (page  377). 

Salts  of  Quinine. 

Quinine  is  a  strong  base,  completely  neutralising  acids,  and 
forming  crystallisable  salts  having  no  reaction  on  litmus  or  methyl- 
orange.  These  salts  react  with  phenolphthalein  as  if  the  acid 
were  in  an  uncombined  state.  Quinine  also  forms  a  series  of  acid 
salts,  of  which  the  acid  sulphate  of  quinine  is  the  type. 

Several  of  the  salts  of  quinine  are  official  in  the  Pharmacopoeiay 
and  others  are  extensively  used  in  medicine. 

Quinine  Sulphate.  Diquinic  sulphate.  (C2oH24N'2^2)2-^2^^4-  '^^^^ 
important  salt,  sometimes  called  "  d  i  s  u  1  p  h  a  t  e  "  or  "basic 
sulphate"  of  quinine,  forms,  in  the  hydrated  state,  the  ordinary 
medicinal  sulphate  of  quinine  of  commerce. 

Sulphate  of  quinine  is  usually  met  with  in  exceedingly  light 
scales,  or  long,  flexible  filiform  needles,^  having  a  nacreous  aspect 
and  a  pure  and  intensely  bitter  taste. 

The  crystallised  sulphate  of  quinine  of  commerce  usually  con- 
tains about  14"5  per  cent,  of  water,  a  proportion  which  corre- 
sponds closely  to  a  7-atom  hydrate,  which  requires  14'45  per  cent. 
According  to  some  authorities,  however,  the  wholly  uneffloresced 
crystals  contain  8  aqua,  or  at  any  rate  7^  aqua.^     H.  B.  Parsons 

^  Chemically  pure  quinine  sulphate,  free  from  h)-droquinine,  crystallises  in 
heavy  needles  resembling  sulphate  of  zinc.  The  light  character  of  the  com- 
mercial salt  is  chiefly  due  to  the  presence  of  small  admixtures  of  the  sulphates 
of  hydroquinine  and  cinchonidine,  and  possibly  of  hydrocinchonidine  and 
homocinchonidine.  One  per  cent,  of  cinchonidine  is  sufficient  to  produce  the 
light  silky  appearance,  and  this  persists  with  a  larger  proportion.  "  A  few 
years  ago,  when  the  bark  of  Remijia,  which  contains  no  cinchonidine,  was 
first  treated,  the  latter  alkaloid  was  added,  as  the  pure  solutions  yielded  large 
brilliant  needles  unfamiliar  in  commerce  ;  for  the  same  reason  the  bark  of 
cuprea  was  never  treated,  except  by  being  mixed  with  other  barks."  The  sul- 
phates of  the  bases  of  the  cinchonidine  group  can  be  separated  from  quinine 
sulphate  without  interfering  with  its  light  form  when  there  is  a  sufficient  amount 
of  hydroquinine  present.  According  to  Carles,  an  addition  of  4  grammes  of 
ammonium  sulphate  to  1  litre  of  a  hot  saturated  solution  of  quinine  sulphate 
causes  the  latter  salt  to  crystallise  on  cooling  in  a  very  voluminous  form. 

^  The  British  Pharmacopoeia  of  1885  gives  the  formula  of  crystallised 
quinine  sulphate  as  (B2H2S04)2l5H20,  which  corresponds  to  1\  aqua.  The 
freshly  prepared  salt  is  stated  to  lose  15 '2  per  cent,  of  water  when  dried  at  the 
temperature  of  boiling  water. 


QUININE   SULPHATE.  407 

{Proa.  Amer.  Pharm.,  xxxii.  457)  has  published  the  results  of 
drying  for  three  hours,  at  100°,  1015  samples  of  quinine  sulphate 
(taken  from  tins  holding  100  ounces  each,  and  not  previously- 
opened)  of  American,  German,  and  Italian  manufacture.  The 
average  loss  of  water  was  13 '8 4  per  cent.,  the  highest  average  from 
any  one  maker  being  14  "3  6  per  cent.  A.  J.  Gown  ley  {Pharm. 
Jour.,  [3],  xvi.  797)  found  the  water  in  thirty-seven  samples  of 
commercial  quinine  sulphate  examined  during  the  two  years  prior 
to  1886  to  range  from  8-10  to  16'12  per  cent.  D.  Hooper 
states  that  the  water  ranges  from  5  to  1 8  per  cent.  Hesse  {Ber., 
xiii.  1517)  states  that  pure  crystallised  quinine  sulphate,  which 
has  not  effloresced,  contains  8H2O,  or  16*17  per  cent,  of  water. 
Ginchonidine  sulphate,  on  the  contrary,  crystallises  with  6H2O,  or 
13*7  per  cent.  Hence,  if  a  sample  of  quinine  sulphate  be  dry  and 
quite  free  from  efflorescence,  the  proportion  of  water  is  an  indica- 
tion of  its  purity. 

Grystallised  quinine  sulphate  is  rendered  perfectly  anhydrous  by* 
exposure  to  a  temperature  of  100°  G.  If  a  higher  temperature  be 
employed  for  its  dehydration,  there  is  a  danger  of  some  of  the 
alkaloid  undergoing  conversion  into  quinicine  (see  page  434).  If 
the  anhydrous  sulphate  of  quinine  be  exposed  to  moist  air,  it 
rapidly  absorbs  from  4*8  to  5  per  cent,  of  water,  a  proportion 
which  corresponds  to  the  formula  BgHgSO^-fSHgO.-^  On  the 
other  hand,  the  crystallised  salt  rapidly  loses  water  on  exposure  to 
air,  until  it  acquires  the  composition  of  the  2-atom  hydrate.  The 
same  quantity  of  water  is  retained  when  the  crystallised  salt  is 
dried  over  sulphuric  acid,  or  crystallised  from  strong  alcohol. 

Quinine  sulphate  requires  750  parts  of  cold  water  for  solution,  but 
dissolves  in  about  30  parts  of  water  at  100°  G.  It  is  far  less  soluble 
in  water  containing  sulphate  of  magnesium,  sodium,  or  ammonium 
than  in  pure  water.  In  a  strong  solution  of  Rochelle  salt,  quinine 
sulphate  is  so  little  soluble  that  the  alkaloid  can  scarcely  be  detected 
by  the  fluorescence  or  thalleioquin  test.  On  the  other  hand,  the 
solubility  of  sulphate  of  quinine  in  water  is  increased  by  the  pre- 
sence of  ammonium  chloride,  or  of  potassium  nitrate  or  chlorate. 

In  alcohol,  quinine  sulphate  dissolves  more  readily  than  in 
water,  requiring  only  7  or  8  parts  at  a  boiling  temperature,  but  it 
is  much  less  soluble  in  cold  spirit  (see  "Tincture  of  Quinine," 
page  423).  Quinine  sulphate  dissolves  in  about  24  parts 
of  cold  glycerin,  the  solution  being  precipitated  by  addition  of 
water.     Crystallised  quinine  sulphate  is  not  soluble  in  fixed  oils, 

*  H.  P.  Parsons  recommends  the  official  adoption  of  this  hydrate  as  a 
definite  and  stable  form  of  quinine  sulphate. 


408  QUININE  SULPHATE. 

ether,  chloroform,  or  petroleum  spirit.  (It  is  said  to  dissolve  in 
benzene.)  In  the  anhydrous  state,  1  part  of  quinme  sulphate  is 
soluble  in  about  1000  parts  of  chloroform  (see  page  416). 

In  dilute  sulphuric  acid,  quinine  sulphate  is  readily  soluble,  owing 
to  the  formation  of  acid  sulphate  of  quinine,  CgoHg^NgOgjHgSO^. 
This  salt  is  readily  obtainable  in  crystals  containing  THgO.  The 
crystallised  salt  loses  6  aqua  in  the  exsiccator,  and  becomes 
anhydrous  at  100°  C.  When  heated  to  about  135°  C.  it  melts, 
and  is  converted  into  the  corresponding  compound  of  quinicine  (see 
page  434).  Acid  sulphate  of  quinine  dissolves  in  11  parts  of 
cold  water,  and  more  readily  in  hot  water  or  in  alcohol  to  strongly 
fluorescent  solutions. 

From  a  solution  of  quinine  in  excess  of  dilute  sulphuric 
acid,  an  acid  sulphate  may  be  obtained,  having  the  composition 
ajl^^fi^m^^O,,  +  THjO  (=C2oH2,NA,H,SO,  +  H,SO,  + 
TH^O). 

Normal  quinine  sulphate  has  a  specific  rotation  in  alcoholic  solu- 
tion of  Si>=  191*5°,  calculated  for  the  anhydrous  salt.  Excess  of 
acid  increases  the  rotatory  power.  When  dissolved  in  water 
acidulated  with  hydrochloric  acid,  the  value  of  S^  at  15°  is  233*75° 
(Hess  e). 

Sulphate  of  quinine  is  largely  employed  as  a  febrifuge  and  tonic, 
the  official  dose  ranging  from  1  to  10  grains.  It  has  marked 
antiseptic  properties. 

The  fluorescence  of  sulphate  of  quinine  is  considered  on  page 
400  ;  its  reaction  with  iodine  on  page  403  ;  and  with  the  thaUeio- 
quin  test  on  page  401. 

Examination  of  Commercial  Quinine  Sulphate. 

The  salts  of  quinine,  except  the  tannate  (page  420),  can  all  be 
examined  by  the  following  methods  applicable  to  the  sulphate  of 
quinine,  provided  they  are  first  treated  with  10  parts  of  boiling 
water  and  their  own  weight  of  sodium  sulphate.  The  sulphate 
of  quinine  which  deposits  on  cooling  and  the  mother-liquor  obtained 
can  then  be  examined  in  the  usual  way. 

Commercial  sulphate  of  quinine  was  formerly  subject  to  adultera- 
tions of  a  very  gross  character.  Among  the  bodies  employed  to 
sophisticate  it  are  said  to  have  been  starch,  gum,  stearin,  salicin, 
phloridzin,  sugars,  sulphate  of  magnesium,  sulphate  of  sodium,  chalk, 
asbestos,  boric  acid,  &c.  Some  of  these  additions  are  apocryphal 
and  the  majority  are  certainly  obsolete. 

Mineral  additions  would  be  readily  recognised  on  igniting  the 
sample,  which,  when  pure,  will  leave  no  sensible  ash.  Starch, 
chalk,  stearin,  and  boric  acid  would  remain  insoluble  on  treating 
the  substance  with  cold  dilute  sulphuric  acid,  and  gum  would  be 


ADULTERATIONS  OF   QUININE  SULPHATE.  409 

precipitated  on  adding  excess  of  alcohol  to  the  solution  thus 
obtained.  Soluble  impurities  generally  may  be  detected  and  esti- 
mated by  dissolving  the  sample  in  hot  water  and  adding  excess  of 
baryta  water.  The  alkaloid  is  then  removed  by  agitation  with 
ether.  After  removing  the  ethereal  layer,  a  stream  of  carbonic 
acid  is  passed  through  the  aqueous  liquid  to  precipitate  the  excess 
of  baryta,  and  the  whole  well  boiled  and  filtered.  Sulphate  and 
carbonate  of  barium  will  be  left  insoluble,  and  the  filtrate  will  con- 
tain any  sugar  or  other  soluble  impurity  present  in  the  original 
sample,  and  the  observation  of  the  weight  of  the  residue  left  on 
evaporation  will  allow  of  a  determination  of  the  amount.  In 
presence  of  sugar  the  liquid  will  exert  a  dextro-rotatory  action,  and 
in  presence  of  salicin  a  Isevo-rotatory  action  on  polarised  light. 

Treatment  of  the  original  solid  sample  with  concentrated  sul- 
phuric acid,  attended  by  gentle  warming,  will  sufiice  for  the  quali- 
tative detection  of  some  impurities.  Sugar  and  mannite  will 
become  charred,  while  salicin  developes  a  striking  red  colour. 
Good  commercial  quinine  sulphate  dissolves  with  faint  yellow 
colour  in  strong  sulphuric  acid,  and  the  tint  is  not  deepened  on 
warming  gently. 

Similar  general  impurities  may  be  rapidly  tested  for  by  a  test 
devised  by  Hesse,  and  described  on  page  417.  Salicin^  if  present 
in  greater  proportion  than  1  per  cent.,  may  be  detected  by 
this  test.  The  residue  insoluble  in  the  chloroform-mixture  will 
be  coloured  deep  red  by  ccjncentrated  sulphuric  acid,  and  will 
reduce  Feb  ling's  solution  after  boiling  with  dilute  sulphuric  acid. 
The  reaction  with  strong  sulphuric  acid  will  be  produced  by  the 
original  sample  if  the  proportion  of  salicin  be  considerable. 
Smaller  proportions  of  salicin  may  be  detected  in  the  filtrate  from 
the  precipitate  produced  by  adding  baryta  to  the  aqueous  solution 
of  the  sample.  Another  test  for  salicin  is  to  dissolve  0'25  gramme 
of  the  sample  in  4  c.c.  of  water  and  4  drops  of  concentrated  hydro- 
chloric acid.  If  salicin  be  present,  on  boiling  the  liquid  for  some 
minutes  a  white  turbidity  will  be  produced,  due  to  the  formation 
of  s  a  1  i  r  e  t  i  n. 

Sulphate  of  quinine  has  occasionally  been  largely  adulterated 
with  or  entirely  substituted  by  the  hydrochloride  of  cinchonine. 
This  fraud  is  recognisable  by  testing  for  chlorides  with  nitric  acid 
and  nitrate  of  silver,  and  for  cinchonine  as  described  on  page  413. 

The  most  common  impurity  of  commercial  sulphate  of  quinine 
is  an  admixture  of  one  or  more  of  the  sulphates  of  other  cinchona 
alkaloids,  especially  cinchonidine.  This  admixture  is  often  purely 
accidental,  owing  to  imperfect  separation  of  the  other  alkaloids 
during  manufacture,  but  is  no  doubt  sometimes  provided  for  and 


410  COMMERCIAL   QUININE   SULPHATE. 

secured  by  suitable  arrangements  of  the  manufacturing  operations, 
while  occasionally  an  intentional  admixture  of  other  alkaloids  has 
occurred. 

Manufacturers  of  quinine  sulphate  produce  at  least  four  quali- 
ties of  the  article.  (1)  The  pure  salt  or  "heavy  sulphate,"  of 
which  the  use  has  been  hitherto  extremely  limited,  chiefly  on 
account  of  its  unfamiliarity  to  the  members  of  the  medical  pro- 
fession ;  (2  and  3)  products  satisfying  the  requirements  of  the 
German,  and  Dutch  Fliarmacopmias ;  and  (4)  products  satisfying 
others  than  the  above-mentioned  pharmacopoeias,  and  containing 
from  4  to  6  per  cent,  of  sulphate  of  cinchonidine.  Other  products 
may  have  a  certain  commercial  importance,  but  have  no  "legal 
status  "  in  civilised  countries. 

The  best  samples  of  commercial  quinine  sulphate  are  seldom  free 
from  cinchonidine,  but  contain  not  more  than  2  or  3  per  cent. ; 
whilst  other  kinds  contain  from  5  to  10,  and  even  20  per  cent,  of 
cinchonidine  sulphate,  and  on  one  occasion  B.  H.  Paul  found  60 
per  cent. 

F.  W.  Fletcher  (1882)  states  that  quinine  of  English 
manufacture  is  usually  practically  free  from  cinchonidine,  but  that 
certain  foreign  brands  always  contain  from  10  to  15  per  cent.,  in 
one  case  the  proportion  exceeding  25  per  cent.  A.  J.  Cownley 
has  published  determinations  of  cinchonidine  made  by  a  reliable 
process,  and  finds  the  proportion  to  range  from  nil  to  13*9  per 
cent.,  the  next  largest  amount  being  9"0  per  cent.  More  recently 
(1889),  Paul  and  Cownley  {Pharm.  Jour.,  [3],  xix.  665) 
found  the  cinchonidine  sulphate  present  in  twenty-three  typical 
samples  of  quinine  sulphate,  representing  all  the  different  makers, 
to  range  from  nil  (in  two  instances)  to  12*34  per  cent.  In  fourteen 
out  of  the  twenty-three  the  proportion  of  impurity  was  less  than 
6  per  cent.  The  two  samples  which  were  wholly  free  from  cin- 
chonidine were  probably  manufactured  from  cuprea  bark,  which 
is  characterised  by  the  absence  of  cinchonidine,  and  in  one 
instance  this  conjecture  was  confirmed  by  the  detection  of  a  trace 
of  cupreine  in  the  sample.  In  addition,  hydroquinine  is  a  very 
constant  impurity  in  quinine  sulphate,  a  very  notable  proportion 
being  sometimes  present,  and,  according  to  Hesse,  hydrocinchonidine 
and  homocinchonidine  may  also  be  met  with  in  quinine  from  cer- 
tain sources.  The  presence  of  even  1  per  cent,  of  cinchonine  or 
quinidine  in  quinine  sulphate  is  far  more  likely  to  be  intentional 
than  due  merely  to  accident  or  careless  manufacture,  but  these 
alkaloids  are  apt  to  be  met  as  accidental  impurities  in  quinine 
hydrochloride. 

The  detection  and  estimation  of  foreign  alkaloids  in  commercial 


ASSAY   OF  QUININE   SULPHATE.  411 

sulphate  of  quinine  has  received  much  attention,  and  considerable 
ingenuity  has  been  exercised  in  the  solution  of  this  somewhat 
difficult  problem. 

The  recognised  methods  of  testing  commercial  quinine  sulphate 
for  admixtures  of  other  alkaloids  are,  for  the  most  part,  based  on 
the  removal  of  the  greater  part  of  the  quinine  as  a  sparingly  solu- 
ble sulphate,  and  the  distinction  of  the  remaining  quinine  from  its 
associates  by  its  greater  solubility  in  ether  and  its  solubility  in 
excess  of  ammonia.  A  great  variety  of  tests  based  on  these  principles 
have  been  devised,  especially  for  recognition  and  estimation  of  cin- 
chonidine,  the  detection  and  determination  of  the  other  alkaloids 
when  present  in  notable  proportion  presenting  comparatively  little 
difficulty. 

The  separation  of  small  proportions  of  cinchonidine  from  quinine 
is  particularly  troublesome,  and  formerly  any  considerable  propor- 
tions of  the  admixture  must  have  escaped  recognition.  B.  H. 
Paul  (Pharm.  Jour.,  [3],  vii.  653)  has  shown  that  when  the 
test  for  quinine  sulphate  prescribed  in  the  British  Pharmacopoeia 
of  1867  is  rigidly  adhered  to,  it  is  difficult  to  detect  an  admix- 
ture of  20  per  cent,  of  the  cinchonidine  salt.  By  reducing  the 
volume  of  ether  used,  any  impurity  in  excess  of  10  per  cent,  may 
be  detected,  but  less  than  this  proportion  escapes  recognition,  owing 
to  the  property  possessed  by  quinine  of  increasing  the  solubility 
of  cinchonidine  in  ether,  or  at  any  rate  of  preventing  the  latter 
from  separating  in  a  crystalline  state.  Hence,  for  the  detection 
of  small  proportions  of  cinchonidine,  it  is  necessary  first  to  separate 
the  greater  part  of  the  quinine.  This  may  be  done  by  utilising 
the  fact  that  quinine  sulphate  requires  about  750  parts  of  cold 
water  for  solution,  while  cinchonidine  sulphate  is  soluble  in  100 
parts.  This  principle  was  originally  employed  byKern.er,  but 
its  application  has  been  modified  and  improved  in  several  respects 
by  Paul  (Pharm.  Jour.,  [3],  vii.  653;  xvii.  645),  and  Hesse 
(Pharm.  Jour.,  [3],  xvii.  975).  But  cold  water  does  not  completely 
dissolve  cinchonidine  sulphate  from  commercial  quinine  sulphate, 
according  to  Hesse,  because  of  its  existence  in  the  form  of  a  double 
sulphate  of  the  two  alkaloids.  This  compound  is  decomposed  or 
disintegrated  by  hot  water,  even  if  the  quantity  of  liquid  be  in- 
sufficient for  its  solution,  the  cinchonidine  salt  passing  almost 
wholly  into  solution,  while  the  quinine  sulphate  is  for  the  most 
part  undissolved.  On  the  point  whether  it  is  better  to  treat  the 
sample  with  water  at  60°  or  to  100°  C,  authorities  are  at  variance. 
Hesse  considers  that  at  a  boiling  heat  more  of  the  quinine  sulphate 
will  pass  into  solution,  and  hence  there  will  be  a  greater  tendency 
to  the  re-formation  of  the  double  salt  when   crystallisation   takes 


412  ASSAY   OF   QUININE   SULPHATE. 

place.  Kernel  and  Weller  also  recommend  the  use  of  water  at 
60°.  E.  J  u  n  g  fl  e  i  s  c  h  {Jour.  Pharm.  et  Chim.,  [5],  xv.  5  j 
Fharm.  Jour.,  [3],  xvii.  585)  gives  the  preference  to  a  boiling 
temperature,  and  points  out  the  tendency  to  erratic  results  if  less 
heat  be  employed.  Paul  (Pharm.  Jour.,  [3],  xvii.  595)  con- 
siders that  the  best  results  can  only  be  obtained  by  using  nearly 
sufficient  water  to  effect  the  complete  solution  of  the  quinine 
sulphate  at  the  boiling-point. 

The  mode  of  operating  recommended  by  Hesse  is  to  take 
1  gramme  of  quinine  sulphate  previously  dried  at  100°,  shake  it 
with  20  c.c.  of  water  at  60°  C,  filter  after  cooling,  and  agitate 
6  c.c.  of  the  filtrate  in  a  narrow  tube  with  1  c.c.  of  ether  and 
5  drops  of  ammonia  (sp.  gr.  0*96).  The  clear  ethereal  solution 
thus  obtained  should  not  deposit  crystals  on  standing.  If,  on 
leaving  the  tube  at  rest  and  in  a  closed  condition  for  two  hours, 
the  ethereal  stratum  be  found  free  from  crystals,  the  sample  may 
be  considered  pure ;  but  if  it  contain  more  than  0'25  per  cent,  of 
cinchonine  sulphate,  0*5  of  quinidine  sulphate,  or  I'O  per  cent,  of 
cinchonidine  or  homocinchonidine  sulphate,  a  distinct  separation 
of  crystals  wiU  occur.  The  last  two  impurities  appear  granular, 
while  crystals  of  cinchonine  and  quinidine  form  concentric  groups 
of  delicate  needles.  If  the  proportion  of  cinchonidine  be  as  high 
as  3  per  cent.,  the  separation  of  crystals  will  occur  immediately,  or 
■within  three  minutes ;  2  per  cent,  will  show  in  about  ten  minutes ; 
while  with  less  than  1  per  cent,  no  separation  will  occur  even 
after  twelve  hours.  ^  To  detect  smaller  proportions  of  these 
alkaloids,  the  cork  of  the  tube  should  be  replaced  by  a  loose  plug 
of  cotton-wool,  so  that  the  ether  may  gradually  evaporate.  On 
examining  the  residue  with  a  lens  it  will  appear  distinctly 
crystalline  if  J  per  cent,  of  cinchonidine  or  homocinchonidine 
sulphate  be  present,  and  a  mere  trace  will  be  recognisable 
by  the  presence  of  a  few  crystals  in  the  amorphous  mass  of 
quinine.  0*5  per  cent,  of  cinchonine  sulphate,  or  1*0  per  cent, 
of  quinidine  sulphate,  will  cause  an  almost  immediate  separa- 
tion of  crystals  from  the  ether.  Their  presence  is  far  more 
likely  to  be  intentional  than  merely  accidental  or  due  to  careless 
manufacture. 

The  British  Pharmacopoeia  of  1885  gives  the  following  methods 
of    testing    commercial    sulphate    of    quinine    for    accompanying 

^  A  deposit  of  cinchonidine  is  recognised  by  the  capillary  rising  of  the  pre- 
cipitate beyond  the  ethereal  layer  immediately  after  shaking  the  solution. 
"With  a  large  proportion  of  cinchonidine  a  white  chalky  ring  appears  at  the 
line  of  contact  of  the  two  liquids. 


ASSAY   OF   QUININE  SULPHATE.  413 

alkaloids.^  The  salt  "  should  not  contain  much  more  than  5  per 
cent,  of  other  cinchona  alkaloids  "  : — 

a.  Test  for  ClncUonidine  and  Cinchonine.  Heat  100  grains  of 
the  sample  in  5  or  6  ounces  of  boiling  water,  with  3  or  4  drops  of 
dilute  sulphuric  acid.^  Set  the  solution  aside  until  cold.  Separate 
by  filtration  the  purified  crystals  of  quinine  sulphate  which  crys- 
tallise out.  To  the  filtrate,  which  should  nearly  fill  a  bottle  or 
flask,  add  ether,  shaking  occasionally,  until  a  distinct  layer  of 
ether  remains  undissolved.  Then  add  ammonia  in  very  slight 
excess,  and  shake  thoroughly,  so  that  the  quinine  at  first  pre- 
cipitated shall  be  redissolved  by  the  ether.  Close  the  flask,  and 
allow  it  to  stand  for  some  hours,  and  then  remove,  with  a  pipette, 
the  supernatant,  clear,  ethereal  layer  which  should  occupy  the  neck 
of  the  flask.  Agitate  the  residual  aqueous  liquid  and  the  separated 
crystals  of  alkaloid  once  or  twice  with  a  very  little  ether.  Collect 
the  separated  alkaloid  on  a  tared  filter,  wash  it  with  a  little  ether, 
dry  at  100°  C,  and  weigh.  Four  parts  of  the  product  represent 
five  of  crystallised  sulphate  of  cinchonine  or  cinchonidine  in  the 
sample. 

h.  Test  for  Cupreine.  Shake  the  crystallised  sulphate  of  quinine 
obtained  in  Test  a  with  1  fluid  ounce  of  ether  and  \  fluid  ounce  of 
ammonia  (sp.  gr.  0*959),  separate  the  ethereal  solution,  and  add  to 
it  the  ethereal  solution  and  washings  obtained  in  Test  a.  Shake 
the  united  ethereal  liquid  with  IJ  fluid  ounce  of  caustic  soda 
solution  (10  per  cent.),  adding  water  if  any  solid  matter  separates. 
Separate  the  ethereal  layer,  agitate  the  aqueous  liquid  with  more 
ether,  and  separate  as  before.  Heat  the  aqueous  liquid  to  boiling, 
and  exactly  neutralise  it  with  dilute  sulphuric  acid.  Allow  the 
solution  to  cool,  separate  any  crystalline  cupreine  sulphate  by  a 
tared  filter,  wash  with  a  little  cold  water,  dry  and  weigh. 

c.  Test  for  Quinidine.     Recrystallise  50  grains  of  the  sample  as 

^  The  French  Codex  of  1884,  making  use  of  Earner's  method  of  analysis, 
prescribes  that  5  c.c.  of  a  mother- liquor  obtained  at  15°  C,  after  treatment  of 
1  gramme  of  the  officinal  salt  with  10  c.c.  of  luke-warm  water,  shall  remain 
perfectly  limpid  for  24  hours  after  the  addition  of  7  c.c.  of  a  solution  of 
ammonia  of  0  96  specific  gravity.  The  manufacturers  considered  these  regula- 
tions severe.  However,  the  new  Austrian  Pharmacopoeia  prescribes  the  use  of 
7  o.c  of  ammonia,  which  is  only  slightly  less  severe  a  test ;  and  the  pharma- 
copceias  of  Russia,  Finland,  Sweden,  the  United  States,  and  Japan  have 
adopted  nearly  the  same  test.  The  Dutch  Pharmacopoeia  has  reduced  the 
amount  of  ammonia  to  5  c.c,  and  the  German  Pharmacopoeia  of  1890  to  4  c.c. 

2  This  addition  of  sulphuric  acid  is  objectionable,  as  tending  to  increase  the 
solubility  of  the  quinine  sulphate  and  diminish  the  delicacy  of  the  test.  It 
would  be  better  to  direct  the  addition  of  just  sufficient  acid  to  render  the 
solution  faintly  acid  to  litmus. 


414  ASSAY   OF  QUININE  SULPHATE. 

just  described  in  Test  a,  and  to  the  filtrate  add  a  strong  solution 
of  potassium  iodide,  and  a  little  rectified  spirit  to  prevent  the  pre- 
cipitation of  the  hydriodides  of  amorphous  bases.  Collect  the 
precipitate  of  qiiinidine  hydriodide,  wash  it  with  a  little  cold 
water,  dry  at  100°,  and  weigh.  "  The  weight  represents  about  an 
equal  weight  of  crystallised  sulphate  of  quinidine." 

The  foregoing  tests  are,  of  course,  not  intended  for  the  detection 
and  estimation  of  minute  traces  of  accompanying  alkaloids  in 
quinine  sulphate.  Cinchonidine  has  about  one-fourth  the  potency 
of  quinine,  and  hence  the  therapeutic  value  of  the  preparation  is  not 
so  greatly  affected  by  a  small  admixture  as  is  the  commercial  value. 

B.  H.  Paul  {Pharm.  Jour.^  [3],  xvii.  647)  points  out  that  the 
delicacy  of  the  test  would  be  much  increased  by  evaporating  the 
filtered  aqueous  solution  to  about  one-fifth  of  its  volume  before 
shaking  with  ether  and  ammonia.^  Operating  in  this  manner,  as 
small  a  proportion  as  1  per  cent,  of  cinchonidine  sulphate  can  be 
detected  with  certainty,  even  when  only  10  grains  of  the  sample  is 
employed,  provided  that  the  closed  tube  (employed  with  smaU 
quantities  instead  of  a  flask)  be  allowed  to  stand  for  at  least  twelve 
hours  for  the  formation  of  the  crystals.  De  Yrij  {Chem.  Qentr,^ 
1885,  968)  has  suggested  the  addition  of  sufficient  sulphuric  acid 
to  convert  the  bases  into  acid  salts  before  separating  them  by  frac- 
tional solution  and  crystallisation.  Hesse  {Pharm.  Jour.,  [3],  xvii. 
486),  who  expresses  a  high  opinion  of  this  method  if  carefully  per- 
formed, recommends  the  following  mode  of  operating : — 5  grammes 
weight  of  the  sample  is  dissolved  by  the  aid  of  heat  in  12  c.c.  of 
normal  sulphuric  acid  (49  grammes  H^SO^  per  litre)  contained  in 
a  small  porcelain  basin,  and  the  solution  poured  into  a  funnel  closed 
at  the  bottom,^  in  which  it  is  allowed  to  cool.  At  the  end  of  two 
hours  crystallisation  is  complete,  the  stopper  is  removed,  and  the 
mother-liquor  allowed  to  drain  away  as  completely  as  possible,  its 
removal  being  assisted  by  suction.  The  upper  portion  of  the 
crystals  is  then  pressed  down  with  a  glass  rod  and  washed  with 
3  c.c.  of  cold  water,  added  drop  by  drop  while  the  suction  is  kept 
up.  The  whole  solution  is  then  mixed  with  16  c.c.  of  ether  (sp. 
gr.  0"721   to  0*728)  and  shaken  up.^     Three  c.c.  of  ammonia  (sp. 

^  111  a  later  paper  {Pharm.  Jour.,  [3],  xix.  66,5)  Paul  and  Cownley  recom- 
mend that  the  solution  should  be  concentrated  to  about  1  fluid  drachm  (3^  c.c), 
and  the  deposited  crystals  separated  before  treatment  with  ammonia  and  ether. 

2  This  may  be  conveniently  eflFectod  by  a  glass  rod  introduced  from  above, 
and  having  the  lower  end  covered  with  a  short  length  of  india-rubber  tubing. 
The  same  rod  can  be  afterwards  used  for  pressing  down  the  crystals. 

3  If  the  sample  contain  more  than  10  per  cent,  of  cinchonidine  the  volume 
of  ether  must  be  increased. 


ASSAY  OF  QUININE  SULPHATE.  415 

gr.  0*960)  is  next  added,  and  the  whole  well  shaken  again.  After 
standing  one  day  the  ether  is  removed  witli  a  pipette,  and  the 
crystals  which  have  separated  are  collected  on  a  filter  and  washed 
with  water  saturated  with  ether.  The  filter  is  then  placed  on  an 
absorbent  surface,  the  crystals  again  washed  with  some  ether,  and 
dried  at  100°.  These  crystals  are  not  pure  cinchonidine,  but  a 
compound  of  quinine  and  cinchonidine,  having  the  composition 
^20^24-^2^2' ^^19 ■^22-^2^*  There  is  always  a  certain  amount  of 
adhering  quinine,  especially  when  the  proportion  of  cinchonidine 
in  the  sample  is  very  small,  and  hence  Hesse  recommends  that  the 
weight  obtained  should  be  multiplied  by  0'62,  instead  of  by  0  Qid^ 
which  is  the  calculated  factor  for  the  above  formula.^ 

B.  H.  Paul  (Pharm..  Jour.,  [3],  xvii.  555)  strongly  objects  to 
the  acid  sulphate  test,  on  the  ground  that  the  crystals  of  acid 
sulphate  are  not  free  from  cinchonidine,  while  the  amount  of 
quinine  retained  in  solution  is  so  much  increased  as  to  interfere 
with  the  subsequent  crystallisation  of  the  cinchonidine  from  ether. 

Conversion  of  quinine  into  and  crystallisation  as  the  acid  sulphate 
effects  a  separation  of  hydroqidnine,  which  remains  in  the  mother- 
liquor,  while  repeated  recrystallisation  of  the  neutral  sulphate  fails 
to  effect  this  (compare  page  424). 

A  method  of  assaying  quinine  sulphate  for  cinchonidine,  based 
upon  the  optical  rotation  of  the  solution,  has  been  recommended 
by  several  eminent  authorities  and  is  equally  distrusted  by  others. 
Oudemans  was  among  the  first  to  experiment  in  this  direction, 
and  Hesse  proposed  a  definite  process  of  assay,  based  on  the 
rotation  of  the  sulphate.  Koppeschaar  proposed  to  employ 
the  tartrates  by  preference,  while  R  H.  Da  vies  oi)erated  on  the 
sulphates.  De  Vrij  has  strongly  recommended  the  optical 
method  of  examination,  giving  preference  to  the  tartrates. 
Jungfleisch  and  Paul  and  C  o  w n  1  e y  have  expressed 
strong  distrust  of  the  optical  method,  considering  it  manifestly 
impracticable  to  determine  proportions  of  1  and  IJ  per  cent,  of 
cinchonidine  in  quinine  sulphate  containing  even  minute  pro- 
portions of  the  cinchonine  and  quinidine  salts ;  and  D.  Howard 
states  that  no  published  method  gives  the  mixed  tartrates  of 
quinine  and  cinchonidine  sufficiently  pure  to  render  the  polarimetric 
assay  absolutely  reliable.  Hesse  has  modified  his  former  high 
opinion  of  the  method,  and  points  out  that  it  is  invalidated  by 
the  presence  of  hydroquinine,  which  is  invariably  present  in 
commercial  quinine  sulphate,  and  is  not  separated  by  converting 
the  bases  into  tartrates. 

^  Hesse's  test-experiments  on  mixtures  of  pure  quinine  and  cinchonidine 
sulphates  in  known  proportions  justify  this  euipiiiciil  factor. 


416  OPTICAL   ASSAY   OF   QUININE   SULPHATE. 

The  presence  of  1  per  cent,  of  hydroquinine  sulphate  reduces 
the  rotation  to  the  same  extent  as  0'42  per  cent,  of  the  cinchoni- 
dine  salt,  and  its  presence  accounts  for  the  excessive  and  discordant 
figures  for  cinchonidine  often  obtained  by  those  who  rely  on  the 
optical  method  of  assay.  Hydroquinine  cannot  be  perfectly  separated 
from  quinine  even  by  repeated  recrystallisations  of  the  neutral 
sulphate,  but  it  can  be  completely  got  rid  of  by  converting  the 
alkaloid  into  the  acid  sulphate  and  recrystallising  this  from  water 
or  alcohol,  when  the  hydroquinine  remains  in  the  mother-liquor 
(compare  page  424). 

For  the  optical  assay,  Koppeschaar  (Zeitsch.  Anal.  Chem.y 
xxiv.  362)  recommends  that  the  quinine  and  cinchonidine  should 
be  converted  into  tartrates  by  precipitating  the  neutral  solution 
with  Eochelle  salt,  and  the  precipitate  washed  with  a  little  cold 
water  and  dried  at  125°— 130°  C. ;  0*400  gramme  of  the  dry  pro- 
duct is  then  dissolved  in  3  c.c.  of  normal  hydrochloric  acid,  and 
the  solution  diluted  with  water  at  15^  C.  to  a  volume  of  20  c.c. 
The  solution  is  placed  in  a  jacketed  tube  kept  at  15°  C,  and  the 
rotatory  power  observed  by  a  polarimeter  employing  monochromatic 
(sodium)  light.     From  the  angular  rotation  the  specific  rotatory 

power  of  the  tartrate  is  then  calculated  by  the  formula  S  =  — — ; 

where  S  is  the  specific  and  a  the  angular  rotation,  and  I  the  length 
of  the  tube  in  decimetres.  From  the  figure  thus  obtained,  the 
percentage  of  quinine  tartrate,  x,  in  the  mixed  tartrate  may  be 
ascertained  by  the  following  (Koppeschaar's)  formula : — 

_100(S-137-67) 
"'"  82-4 

Each  1°  of  diminution  in  the  specific  rotation  below  220*07°  cor- 
responds to  about  1'2  per  cent,  of  cinchonidine  tartrate  in  the  mixed 
tartrates.  The  angular  rotation  is  diminished  by  0*077°  only  by 
the  presence  of  1  per  cent,  of  cinchonidine  tartrate.  Notwith- 
standing the  extreme  accuracy  of  observation  necessary,  Hooper 
(Pharm.  Jour.,  [3],  xvii.  61)  has  found  the  optical  determination 
of  quinine  in  the  mixed  tartrates  to  give  very  satisfactory  results. 
Hesse  found  the  specific  rotation  of  quinine,  hydroquinine,  and 
cinchonidine  tartrates,  for  Oudemans'  concentration  B,  to  be 
respectively,  -212*5°,  -176*9°,  and  -132*0°. 

For  the  detection  of  cinchonine^  or  quinidine  in  quinine  sulphate, 
Hesse  proposes  to  dry  the  salt  at  100°  C,  and  agitate  1  gramme 
with  15  c.c.  of  cliloroform  free  from  alcohol.     The  liquid  is  passed 

i  According  to  Laborde  {Pharm.  Jour.,  [31,  xiii.  684)  the  presence  of 
cinchonine  materially  alters  the  physiological  etiects  of  quinine  salts. 


EXAMINATION   OF  QUININE   SULPHATE.  417 

through  a  small  filter.  If  10  c.c,  on  evaporation  at  a  gentle  heat, 
leave  an  amorphous  residue  weighing  more  than  '035  gramme, 
cinchonine  or  quinidine  sulphate  is  certainly  present.  If  the  residue 
be  crystalline  and  less  than  the  above  weight,  it  may  be  tested  for 
the  foreign  alkaloids  by  heating  it  with  5  c.c.  of  water,  adding  J 
gramme  of  potassium  sodium  tartrate,  cooling,  filtering  from  the 
precipitated  quinine  and  cinchonidine  tartrates,  and  mixing  the 
filtrate  with  an  equal  volume  of  ammonia.  If  quinidine  or  cin- 
chonine be  present,  a  precipitate  will  be  formed,  and  may  be 
further  examined  by  agitation  with  ether  (see  page  412),  or  by 
treatment  with  iodide  of  potassium  (see  page  413).  Sulphate  of 
cinchonidine,  if  present,  will  remain  undissolved  by  the  chloroform, 
but  will  swell  up  into  very  bulky  needles,  which  suck  up  the 
chloroform  like  a  sponge  and  do  not  yield  it  again  without  pressure. 

L.  Schafer  {Arch.  Pharm.,  [3],  xxv.  64,  1033)  has  described 
a  method  of  testing  commercial  quinine  sulphate,  based  upon  the 
precipitation  of  the  boiling  aqueous  solution  by  neutral  potassium 
oxalate.  After  cooling  and  filtering,  the  filtrate  is  tested  by 
addition  of  caustic  soda. 

0.  Schlickum  (Arch.  Pharm.,  [3],  xxv,  128)  has  investi- 
gated De  Yrij's  chromate  method  (page  405),  and  finds  it  appli- 
cable, under  certain  conditions,  to  the  examination  of  quinine 
sulphate.  On  precipitating  a  solution  of  this  or  other  neutral 
quinine  salt  with  neutral  potassium  chromate,  and  filtering  after 
four  or  more  hours,  the  filtrate  remains  clear  on  addition  of  soda, 
if  the  quinine  salt  was  pure.  In  presence  of  J  per  cent,  of 
cinchonine  sulphate,  or  1  per  cent,  of  the  quinidine  or  cinchonidine 
salt,  a  turbidity  is  produced  at  once  or  after  a  time. 

A  test  for  the  purity  of  quinine  sulphate,  devised  by  Hesse 
and  adopted  by  the  German  Pharmacopoeia,  consists  in  heating 
1  gramme  of  the  sample  for  a  short  time  to  40°-50°  C,  in  7  c.c. 
of  a  mixture  of  2  volumes  of  chloroform  and  1  of  absolute  alcohol. 
If  the  sample  be  pure  it  is  completely  dissolved,  and  the  solution 
remains  quite  clear  on  cooling.  Sulphates  of  other  cinchona 
bases  and  various  organic  and  inorganic  impurities  remain 
insoluble  (compare  page  409). 

A  somewhat  similar  test  has  been  described  by  E.  H  i  r  s  c  h  s  o  h  n, 
according  to  which  0'2  gramme  of  the  quinine  sulphate  should  be 
briskly  agitated  with  5  c.c.  of  a  mixture  of  30  parts  of  petroleum 
ether  of  0*680  sp.  gr.  with  70  parts  of  chloroform.  The  liquid  is 
filtered,  and  diluted  with  three  or  four  times  its  volume  of  petroleum 
ether,  when  an  admixture  of  O'l  per  cent,  of  sulphates  of  other 
cinchona  bases  will  give  rise  to  a  turbidity  or  precipitate. 

For  the  detection  of  amorphous  alkaloid  in  commercial  quinine 

VOL.  III.  PART  II.  2  D 


418  QUININE    HYDROCHLORIDE. 

sulphate,  De  Vrij  recommends  the  following  method  : — The  sample 
is  dissolved  in  dilute  acid,  and  shaken  with  ammonia  and  ether  for 
estimation  of  total  alkaloid.  Sufficient  decinormal  oxalic  acid  is 
added  to  the  ether-residue  to  convert  the  alkaloid  into  neutral 
oxalate,  and  the  liquid  is  evaporated  at  a  steam-heat  and  the 
residue  thoroughly  dried  in  the  water-bath.  It  is  then  dissolved 
in  chloroform,  and  the  liquid  filtered  if  necessary.  The  clear  solu- 
tion is  next  treated  in  a  test-tube  with  a  few  drops  of  water,  when 
crystals  of  oxalate  of  quinine  will  appear  in  the  chloroform.  If 
the  sample  w^ere  pure  the  aqueous  layer  will  remain  clear  and 
iincoloured,  but  if  amorphous  alkaloid  be  present  it  wiU  be  dissolved 
by  the  water  and  colour  it  yellow. 

Quinine  Hydrochloride.  Hydrochlorate  of  quinine.  B,HC1. 
This  salt  forms  long  asbestos-like  prisms  containing  2  aqua,  which 
become  anhydrous  at  120°  C.  without  previously  melting.  The 
dehydrated  salt  fuses  at  158°-160°  without  change,  and  is  not 
converted  into  quinicine,  as  stated  by  Pasteur  (Hesse).  If  an 
aqueous  solution  of  quinine  hydrochloride  saturated  at  15°  C.  be 
allowed  to  stand  for  some  time  at  about  0°  C,  large  octahedral 
crystals  containing  3  aqua  separate  out.  Quinine  hydrochloi-ide 
is  soluble  in  about  40  parts  of  cold  water,  and  very  soluble  in  hot 
water  and  in  alcohol. 

Quinine  hydrochloride  has  been  frequently  substituted  of  late 
years  for  the  sparingly  soluble  sulphate.  Thus  it  is  used  in 
making  the  Tincture  of  Quinine,  B.P.  The  hydrochloride  is  the 
more  expensive  salt,  owing  to  the  increased  difficulty  of  crystal- 
lising and  the  high  percentage  of  quinine  contained  in  it  (84*2 
per  cent.,  against  73*5  in  the  crystallised  sulphate). 

Quinine  hydrochloride  is  prepared  by  reacting  on  the  sulphate 
with  chloride  of  barium.^  Hence  it  is  apt  to  contain  either  unde- 
composed  sulphate  of  quinine,  or  else  barium  chloride.  The  latter 
impurity  is,  of  course,  very  objectionable. 

Quinine  hydrochloride  may  be  assayed  in  much  the  same  manner 
as  the  sulphate  (see  page  408  et  seq.).  The  B.P.  test  for  quinine 
sulphate  is  applicable  to  the  examination  of  the  hydrochloride,  if 
the  sample  be  previously  dissolved  in  ten  times  its  weight  of 
boiling  distilled  water,  together  with  its  own  weight  of  crystallised 
sodium  sulphate.  The  crystals  of  quinine  sulphate  which  are 
deposited,  and  the  filtrate   from   them,  can  then   be  examined   as 

^  The  acid  hydrochloride,  BHaClg,  is  obtained  by  precipitating  the  acid 
sulphate  of  quinine  by  barium  chloride.  It  forms  groups  of  concentric 
needles,  which  can  be  dried  without  change  at  110°,  and  are  soluble  in  an  equal 
weight  of  water.  It  also  separates  as  a  gelatinous  mass,  which  becomes 
ciystalline  on  gentle  warming. 


SALTS   OF   QUININE.  419 

described  on  page  412  e^  seq.  The  hydrochloride  of  quinine  is 
more  likely  to  be  contaminated  with  the  similar  salts  of  cinchonine 
and  quinidine  than  with  the  hydrochlorides  of  cinchonidine  and 
homocinchonidine. 

Quinine  hydrochloride  has  on  several  occasions  been  accidentally 
mixed  with  or  replaced  by  the  corresponding  salt  of  morphine. 
The  impurity  may  be  detected  by  warming  the  salt  with  dilute 
nitric  acid,  which  ac(]uires  a  yellow  or  red  colour  if  morphine  be 
present;  or  the  salt  may  be  placed  in  a  porcelain  crucible  and 
moistened  with  very  neutral  ferric  chloride,  which  will  produce  a 
green  or  blue  colour  if  morphia  be  present.  The  production  of  a 
blue  colour  wdth  mixed  solutions  of  ferric  chloride  and  potassium 
ferricyanide  (page  317)  is  also  well  adapted  for  the  detection  and 
approximate  estimation  of  morphine  in  presence  of  cinchona  bases. 
Lastly,  the  aqueous  solution  of  the  salt  may  be  treated  with 
ammonia  and  agitated  with  a  small  quantity  of  ether,  when  any 
morphine  (or  cinchonine)  will  remain  undissolved. 

Quinine  Hydrohromide,  BHBr  +  HgO,  is  prepared  by  mixing 
equivalent  quantities  of  quinine  sulphate  and  potassium  bromide 
with  their  own  weight  of  water,  adding  three  or  four  parts  of 
strong  alcohol,  filtering  from  the  precipitated  potassium  sulphate, 
and  crystallising  the  quinine  hydrobromide  from  the  filtrate.  The 
salt  forms  silky  needles,  soluble  in  16  parts  of  water  to  a  solution 
said  to  be  fluorescent  (?). 

Quinine  Carbonate,  BgHgCOg+HgO,  is  obtained  by  passing 
carbon  dioxide  into  water  containing  freshly  precipitated  quinine 
hydrate,  and  exposing  the  resultant  solution  to  the  air.  It  forms 
translucent  needles,  efflorescing  rapidly  in  the  air,  decomposing  at 
110°  C,  and  soluble  in  water  or  alcohol  but  insoluble  in  ether. 

Quinine  Clir ornate,  B2H2Cr04  +  2H20.  The  anhydrous  salt 
rapidly  re-absorbs  2  aqua  on  exposure  to  air.  It  is  soluble  in  about 
2000  parts  of  cold  water,  and  has  been  recommended  by  d  e  Vrij 
for  the  determination  of  quinine  (page  405).  It  becomes 
anhydrous  at  80",  and  decomposes  at  a  higher  temperature. 

Quinine  Oxalate,  BgHgCgO^  +  ^HgO,  forms  delicate  needles 
soluble  in  about  900  parts  of  cold  water.  The  oxalates  of  the 
other  frequently  occurring  cmchona  bases  are  comparatively  easily 
soluble,  and  L.  Schafer  has  based  on  this  fact  a  method  of  separat- 
ing small  proportions  of  these  boses  from  quinine  (page  417). 

Quinine  Valerate  forms  colourless  rhoraboidal  plates,  having 
a  pearly  lustre  and  a  faint  odour  of  valeric  acid.  It  is  not  deli- 
quescent, and  fuses  at  a  low  temperature.  Quinine  valerate 
requires  110  parts  of  cold  or  40  of  boiling  water  for  solution,  and 
is  easily  soluble  in  alcohol.     Valerate  of  quinine  is  liable  to  con- 


4.20 


QUININE  TANNATE. 


tain  much  the  same  impurities  as  the  sulphate  (see  page  408). 
Sulphate  and  hydrochloride  of  quinine,  and  valerate  and  acetate  of 
zinc  are  also  liable  to  be  present. 

Quinine  Tannate  has  come  into  use  in  medicine  on  account  of 
its  comparatively  tasteless  character.  The  commercial  product 
varies  greatly  in  its  composition,  the  bitter  taste  decreasing  with 
the  amount  of  alkaloid  contained  in  the  specimen. 

For  the  preparation  of  quinine  tannate,  P  e  1 1  z  recommends  the 
precipitation  of  a  saturated  solution  of  1  part  of  quinine  hydro- 
chloride by  3  of  tannin  (in  10  per  cent,  solution  previously 
neutralised  by  ammonia).  After  standing  twenty-four  hours,  the 
washed  precipitate  is  dried  at  a  low  temperature.  So  prepared, 
quinine  tannate  is  a  yellowish-white  amorphous  powder,  soluble  in 
about  50  parts  of  cold  water  or  alcohol.  Its  solution  gives  the 
reactions  of  tannic  acid. 

In  some  cases,  the  quinine  in  the  commercial  tannate  is  largely 
replaced  by  other  cinchona  bases.  The  following  analyses  by 
Jobst  {Arch.  Pharm.,  [3],  xii.  331;  Jour.  Ghem.  Soc,  xxxiv. 
678)  illustrate  the  composition  of  commercial  "tannate  of 
quinine  "  : — 


1 

2 

3 

4 

5 

6 

7 

Water  lost  at  120°  C. 

7-2 

97 

9-1 

9-8 

10-2 

10-7 

11-4 

Quinine, 
Quinidine,    . 
Cinchonidine, 
Cinchouine, 

Total  Alkaloid,     . 

31*37 

22-72 

4-46 

11-97 

7-33 

4-93 

2-43 

13-10 

3-35 

6-23 
Trace. 
•23-80 
Trace. 

10-00 

7-40 

31-37 

22-72 

23-76 

23-82 

27-03 

10-00 

7-40 

To  ascertain  the  proportion  of  total  alkaloid  in  quinine  tannate, 
Jobst  powders  1  gramme  of  the  sample,  and  mixes  it  with  milk  of 
lime.  The  mixture  is  dried  on  the  water-bath,  and  the  resulting 
powder  exhausted  with  chloroform.  The  chloroform  is  filtered, 
evaporated,  and  the  residue  weighed  after  drying  at  120°  C. 
The  alkaloid  thus  separated  can  be  further  examined  as  described 
on  page  412.  There  seems  no  reason  why  the  mixture  of  the 
sample  with  milk  of  lime  should  not  be  agitated  directly  with 
chloroform,  thus  avoiding  the  evaporation  to  dryness  of  the 
aqueous  liquid.  A  similar  process  is  adopted  by  S.  Neumann, 
who  agitates  the  finely  divided  tannate  with  strong  solution  of 
caustic  alkali  and  excess  of  ether.     The  presence  of  solid  particles 


CITE  ATE  OF  IRON   AND  QUININE.  421 

in  suspension,  either  in  the  ethereal  or  alkaline  solution,  shows 
that  the  sample  is  impure  or  that  it  has  not  been  completely 
decomposed. 

8.  Qpdnine  Tartrate,  BgHgC^H^Og  +  HgO,  forms  a  crystalline 
precipitate,  soluble  in  910  parts  of  cold  and  more  readily  in  hot 
water.  It  becomes  anhydrous  at  lOO'',  and  is  the  best  form 
for  observing  the  optical  activity  of  quinine  (page  416). 

Citrate  of  Qninme  is  not  a  commercial  preparation,  but  in  com- 
bination with  ferric  citrate  it  constitutes  the  Ferri  et  Quinince 
Citras,  B.P. 

Citrate  of  Iron  and  Quinine  occurs  in  commerce  in  the  form  of 
thin  transparent  deliquescent  scales,  varying  in  colour  from  a 
delicate  greenish  golden  yellow  to  yellowish  brown,  according  to 
the  proportion  of  ammonium  citrate  present.  The  preparation 
should  be  somewhat  slowly,  but  freely  and  completely,  soluble  in 
cold  water.  It  is  insoluble  in  alcohol  or  ether.  The  aqueous 
solution  has  a  very  bitter  and  chalybeate  taste,  and  should  be  only 
very  slightly  acid.  On  adding  ammonia  to  the  cold  solution,  white 
quinine  hydrate  is  thrown  down,  and  the  liquid  assumes  a  darker 
colour.  No  ferric  hydrate  is  precipitated  unless  the  liquid  be 
heated,  or  a  fixed  alkali  substituted  for  the  ammonia. 

Citrate  of  iron  and  (.quinine  is  liable  to  several  sophistications. 

The  proportion  of  water  in  the  sample  may  be  ascertained  by 
drying  a  weighed  quantity  in  the  water-oven.  It  averages  8  per 
cent.,  and  should  not  exceed  10  to  12  per  cent. 

Adulteration  with  jpotassio-citrate  or  potassio-tartrate  of  iron 
would  be  detected  by  the  strongly  alkaline  reaction  of  the  residue 
left  on  igniting  the  substance,  a  genuine  preparation  yielding  an 
ash  neutral  or  only  very  faintly  alkaline  to  litmus  paper.  The 
substitution  of  tartaric  acid  for  the  citric  acid  of  the  sample  is  now 
improbable,  but  may  be  detected  as  described  in  Volume  I. 

The  proportion  of  oxide  of  iron  can  be  estimated  in  the  pure 
preparation  with  sufficient  accuracy  by  igniting  a  known  weight  of 
the  sample.  After  testing  the  ash  for  fixed  alkali,  a  few  dro])s  of 
nitric  acid  should  be  added  and  the  residue  again  ignited.  This 
treatment  ensures  the  complete  combustion  of  the  carbon.  Citrate 
of  iron  and  quinine  ought  to  yield  from  18  to  20  per  cent,  of 
ferric  oxide  on  ignition.  A  more  accurate  estimation  of  the  iron  can 
be  made  in  the  ash,  if  desired. 

Excess  of  citric  acid  is  indicated  by  the  extra  acidity  of  the 
sample,  but  the  commercial  substance  frequently  contains  a  much 
larger  proportion  of  acid  than  is  prescribed  in  the  British  Phar 
macopoeia. 

Sulphates  ale  almost  invariably  present  in  citrate  oi  iron  and 


422  CITRATE   OF   tRON   AND   QlTINmE. 

quinine,  owing  to  imperfect  washing  of  the  ferric  hydrate  em- 
ployed, or  to  the  introduction  of  the  quinine  as  sulphate  instead  of 
precipitated  hydrate.  The  employment  of  sulphate  of  quinine  is 
said  to  render  the  preparation  liable  to  yield  a  turbid  solution,  but 
it  has  the  advantage  of  preventing  the  inevitable  loss  of  alkaloid 
attending  the  preparation  of  quirdne  hydrate.^ 

The  British  Pharmacopoeia  of  1867  required  that  the  citrate  of 
iron  and  quinine  should  contain  16  per  cent,  of  alkaloid,  as  deter- 
mined by  drying,  at  an  unstated  temperature,  the  unwashed  quinine 
hydrate  precipitated  by  ammonia.  In  the  edition  of  1885,  tliis 
faulty  process  was  substituted  by  a  method  recommended  by  the 
author  {Analyst,  i.  22),  based  on  the  li iteration  of  the  quinine 
from  the  aqueous  solution  by  ammonia  and  extraction  of  the 
alkaloid  by  ether  or  chloroform.^  No  temperature  is  prescribed  for 
drying  the  alkaloidal  residue,  but  a  constant  weiglit  is  best  obtained 
at  110°— 120°.  By  this  process,  which  yields  very  accurate  results, 
the  B.P.  preparation  is  now  required  to  yield  15  per  cent,  of  alka- 
loid.^ If  preferred,  the  residue  may  be  dissolved  in  a  little  alcohol, 
the  solution  diluted  with  water,  and  titrated  with  a  standard  mineral 
acid  and  methyl-orange. 

The  proportion  of  alkaloid  in  the  citrate  of  iron  and  quinine  of 
commerce  is  often  notably  less  than  the  15  per  cent,  required  by 
the  British  Pharmacopoeia  (see  Pharm.  Jour.,  xvii.  234  ;  xix.  259  ; 
XX.   1052).     Very  commonly  only   13  per  cent,  is  present,*  and 

^  F.  W.  Fletcher  states  that  a  preparation  made  with  sulphate  of  quinine 
contains  less  lime  salts  than  when  quinine  hydrate  is  used,  since  the  lime 
salts  introduced  in  the  water  employed  for  washing  the  alkaline  ferric  hydrate 
are  retained  by  the  latter,  and  are  subsequently  precipitated  as  calcium  sul- 
phate, instead  of  remaining  in  the  finished  product. 

*  To  ensure  accurate  results,  the  cold  solution  of  the  sample  must  be  treated 
with  a  considerable  excess  of  ammonia  ;  the  volume  o4"  ether  or  chloroform 
used  should  equal  that  of  the  animoniacal  liquid,  and  the  agitation  should  be 
conducted  imuieiliately  ;  the  treatment  with  the  solvent  should  be  repeated  ; 
and  care  must  be  tiiken  that  the  whole  of  the  precipitated  alkaloid  is  dissolved 
by  the  ether.  This  occurs  instantaneously  with  pure  quinine,  but  if  cincho- 
nine  has  been  substituted  it  will  remain  undissolved.  In  such  samples,  the 
treatment  with  ether  should  be  followed  by  agitation  with  a  mixture  of  4  parts 
of  chloroform  and  1  of  amylic  alcohol. 

^  The  original  issue  o  f  the  1885  edition  of  the  British  Pharmacoposia  required 
16  per  cent,  of  quinine,  as  estimated  by  the  ammonia-ether  process,  but  the 
criticisms  of  F.  W.  Fletcher,  C.  Umney,  and  others  {Pharm.  Jour.,  [3], 
263,  406)  showed  that,  if  prepared  according  to  the  official  directions,  this 
proportion  was  impossible,  and  the  amount  was  subsequently  reduced  to  15 
per  cent. 

^Chas.  Umney  {Pharm.  Jour. ,  [3],  xvii.  235)  considers  that,  the  B. P. 
standard  of  quality  being  easily  attainable,  the  manufacture  of  citrate  of  iron 


TINCTURE   OF   QUININE.  4231 

occasionally  (in  the  author's  experience)  from  9  to  11  per  cent., 
even  in  the  case  of  preparations  manufactured  by  English  firms  of 
fairly  good  repute.  Foreign  specimens  sometimes  contain  only 
4  or  5  per  cent,  of  alkaloid,  and  that  not  quinine. 

The  adulteration  of  citrate  of  iron  and  quinine  is  not  limited  to 
deficiency  of  total  alkaloid,  the  quinine  being  sometimes  replaced, 
without  acknowledgment,  by  other  cinchona  bases.  The  British 
Pharmaco;pceia  prescribes  no  test  for  these,  further  than  requiring 
the  ether-residue  to  be  "  almost  entirely  soluble  in  a  little  pure 
ether."  The  presence  of  these  bases  is  best  detected  by  dissolving 
the  alkaloidal  residue  in  sufficient  dilute  sulphuric  acid  to  convert 
the  bases  into  neutral  sulphates,^  and  treating  the  resultant  solution 
as  described  on  page  4 1 2  e^  seq.  To  obtain  reliable  results  a  consider- 
able quantity  of  the  sample  must  be  employed,  but  nearly  the 
whole  of  the  quinine  is  subsequently  recovered  as  crystallised  sul- 
phate. By  separating  this  on  a  calico-filter,  pressing  it  between 
folds  of  blotting-paper,  and  drying  it  at  100'',  the  anhydrous  sul- 
phate is  obtained,  and  its  weight  multiplied  by  1'18  represents  the 
weight  of  the  crystallised  salt.  If  to  this  amount  there  is  added 
0'00133  gramme  for  each  1  c.c.  of  mother-liquor,  a  very  fair  direct 
determination  of  the  quinine  sulphate  will  be  obtained ;  and  by 
multiplying^  the  result  by  '735  the  corresponding  amount  of  free 
quinine  will  be  found. 

in  foreign  specimens  of  citrate,  substitution  of  the  quinine  by 
other  cinchona  bases  is  common.  Amorphous  alkaloids  are  not 
unfrequently  present  in  considerable  proportion. 

Tincture  of  Quinine,  B.P.,  was  formerly  directed  to  be  made 
by  dissolving  160  grains  of  crystallised  sulphate  of  quinine  in 
20  fluid  ounces  of  tincture  of  orange-peel,  by  the  aid  of  a  gentle 
heat,  the  solution  being  filtered  after  three  days.  This  was  an 
unsatisfactory  preparation,  as  in  cold  weather,  or  when  too  weak  a 
spirit  was  used,  it  was  apt  to  deposit  crystals  of  sulphate  of  quinine, 
and  so  alter  in  strength.  In  some  cases,  at  least,  the  deposit  con- 
sisted largely  of  calcium  sulphate.  In  the  Pharmacopoeia  of  1885 
an  equal  weight  of  quinine  hydrochloride  is  substituted  for  the 
sulphate,  so  that  the  tincture  is  somewhat  stronger  than  the  old 
preparation.    To  determine  the  proportion  of  quinine  in  the  tincture, 

and  quinine  containing  only  13  per  cent,  of  alkaloid,  unless  it  arises  from  some 
accident,  is  a  disgrace  to  pharmacy ;  and  that  any  pharmacist  who  sells  an 
article  of  tliis  character  ought  to  be  punished,  unless  he  can  show  good  cause 
for  the  deficiency. 

1  This  may  be  effected  by  adding  a  moderate  excess  of  hot  dilute  acid,  and 
then  dilute  ammonia,  drop  by  drop,  until  the  liquid  is  neutral  to  methyl- 
orange  or  litmus. 


424  HYDROQUININE. 

1  fluid  ounce  should  be  concentrated,  and  shaken  with  ether  to 
remove  the  essential  oil  of  orange-peel.  After  removing  the  ether, 
the  aqueous  liquid  should  he  cooled,  an  excess  of  ammonia  added, 
and  then  the  whole  shaken  with  ether  in  the  usual  way  (see 
page  402). 

Wine  of  Quinine,  B.P.,  contains  1  grain  of  crystallised  sulphate 
of  quinine  and  1 J  grain  of  citric  acid  in  each  fluid  ounce  of  orange 
wine.  It  is  apt  to  be  debased  by  partial  omission  of  the  quinine 
or  its  replacement  by  other  cinchona   alkaloids.     For  its   assay, 

2  fluid  ounces  may  be  concentrated  to  J  ounce,  and  then  treated 
like  the  tincture  of  quinine  (see  above).  If  the  alkaloid  prove 
insoluble  in  ether,  a  mixture  of  chloroform  and  amylic  alcohol  must 
be  substituted  for  the  ether.  More  reliable  results  are  obtained  by 
titrating  the  ether-residue  with  standard  acid  and  methyl-orange 
than  by  weighing  it,  as  substances  other  than  alkaloids  are  liable  to 
be  extracted. 

Hydroquinine,  CgoHggNgOg,  was  discovered  by  Hesse  {Ber.,  xv. 
856)  in  the  mother-liquors  from  which  quinine  sulphate  had  been 
crystallised,  and  subsequently  in  the  commercial  salt  itself,  in 
which  it  is  sometimes  present  to  the  extent  of  4  per  cent.^ 
Quinine  cannot  be  perfectly  freed  from  hydroquinine  even  by 
repeated  crystallisation  of  the  neutral  sulphates,  but  the  hydro- 
quinine can  be  completely  separated  by  converting  the  alkaloid 
into  the  acid  sulphate  and  recrystallising  this  from  water  or  alcohol, 
when  the  hydroquinine  remains  in  the  mother-liquor. 

As  precipitated  from  a  cold  solution  of  a  salt  by  caustic  soda, 
hydroquinine  is  amorphous,  but  gradually  becomes  crystalline.  In 
the  latter  condition  it  contains  2  aqua,  which  is  driven  off  at  115°. 
From  chloroform  and  ether  the  alkaloid  crystallises  in  delicate 
concentric  groups  of  needles.     It  melts  with  darkening  at  168°. 

Hydroquinine  dissolves  readily  in  alcohol,  ether,  chloroform, 
benzene  and  ammonia,  but  not  in  caustic  alkali  solutions,  and  is 
only  very  sparingly  soluble  in  water. 

Hydroquinine  resembles  quinine  in  its  IsBvo-rotation,  fluorescence 
of  its  acid  solutions,  behaviour  with  the  thalleioquin  test,  and  in  its 
physiological  action.  It  diff'ers  from  quinine  by  only  very  slowly 
decolorising  a  solution  of  potassium  permanganate. 

Crystalline  compounds   of  hydroquinine   with   cupreine,   quini- 

^  The  proportion  of  hydroquinine  in  the  bark  is  very  small,  and  bears  no 
constant  relation  to  that  of  the  quinine.  To  obtain  the  hydroquinine  pure 
the  alkaloids  should  be  repeatedly  crystallised  as  acid  sulphates,  the  residual 
quinine  got  rid  of  by  potassium  permanganate,  the  hydroquinine  liberated 
from  the  filtered  liquid  by  caustic  soda,  extracted  with  ether  or  chloroform, 
and  the  neutral  sulphate  repeatedly  recrystallised  from  boiling  water. 


QUINIDINE.  425 

dine,  cinch onidine,  and  some  other  cinchona  bases  have  been 
obtained  ;  but  not  with  cinchonine  or  hydrocinchonine. 

Hydroquinine  has  the  usual  well-marked  basic  characters  of  the 
cinchona  alkaloids.  BgHgSO^  +  GHgO  forms  short  prisms,  soluble 
in  350  parts  of  cold  water. 

The  tartrate  crystallises  with  2  aqua  in  prisms  which  become 
anhydrous  at  120°  and  are  soluble  in  545  parts  of  water  at  17°  C. 
The  chromate  is  more  soluble  than  the  quinine  salt,  but  crystallises 
with  it,  and  can  only  be  partially  separated  by  boiling  with  water. 
BHCl  +  2  aqua  is  readily  soluble.  On  mixing  its  solution  with 
l^otassium  iodide,  the  liydriodide  separates  as  an  oily  mass  which 
gradually  solidifies  but  does  not  become  crystalline.  The  acid 
saltj  B(HI)2+4aqua,  crystallises  in  brilliant  yellow  needles, 
readily  soluble  in  hot  water  to  a  colourless  solution,  from  which 
the  yellow  salt  separates  again  on  cooling. 

When  heated  to  140°  with  strong  hydrochloric  acid,  hydro- 
quinine  loses  a  methyl  group,  and  is  converted  into  h  y  d  r  o  c  u- 
preine,  C19H24N2O2. 

When  hydroquinine  is  heated  to  140°  with  sulphuric  acid  con- 
taining 25  per  cent,  of  HgSO^  the  alkaloid  is  unchanged ;  but 
when  the  dry  sulphate  is  fused  by  heating  it  to  140°,  the  base 
is  converted  into  amorphous  hydroquinicine  without  altera- 
tion of  weight  or  other  change  of  composition. 

Hydroquinicine  neutralises  acids  completely  and  forms  some 
crystallisable  salts.  When  an  ethereal  solution  of  the  base  is 
gradually  mixed  with  a  solution  of  oxalic  acid  in  ether,  neutral 
hydroquinicine  oxalate  is  formed  as  an  amorphous  brown 
mass,  readily  soluble  in  chloroform  ;  whereas  the  oxalate  of  qui- 
nicine,  obtained  similarly,  forms  a  voluminous  precipitate,  consist- 
ing of  very  minute  needles. 

Hydroquinine- sulplionic  add,  C^^^^{^Ofi)l^jd^-\-^jdi  is  ob- 
tained on  dissolving  hydroquinine  in  cold  concentrated  sulphuric 
acid.  On  diluting  the  solution  with  water  and  neutralising  it  with 
ammonia,  the  sulphonic  acid  separates  in  crystals,  insoluble  in 
ether  or  chloroform  and  sparingly  soluble  in  cold  soda  or  ammonia. 
In  dilute  acids  it  dissolves  readily,  forming  crystallisable  salts. 
The  sulphuric  acid  solution  is  fluorescent  and  responds  to  the 
thalleioquin  test. 

Quinidine.      Conquinine.      C2oH24N2^2- 

This  base  is  isomeric  with  quinine,  and  occurs  frequently  in 
cinchona  barks  (especially  Cinchona  Pitayensis)  in  association  with 
quinine  and  other  alkaloids.  It  also  occurs  in  cuprea  bark  ;  and 
is  present  to  a  considerable  extent  in  commercial  "  quinoidine." 


426  QUINIPINE   SULPHATE. 

Quinidine  (see  also  page  393)  crystallises  from  alcohol  with 
2  J  aqua  in  large  monoclinic  efflorescent  prisms  or  needles.  From 
ether  permanent  rhombohedra  containing  2  aqua  are  obtained,  and 
from  boiling  water  permanent  plates  with  1 J  aqua.  The  whole  of 
the  water  is  driven  off  at  120°.  At  160°  the  anhydrous  alkaloid 
begins  to  brown  slightly,  and  melts  at  168°. 

Quinidine  resembles  quinine  in  its  taste  and  physiological  effects, 
in  being  deposited  in  hydrated  crystals  from  alcohol,  in  its 
tolerably  ready  solubility  in  ether,  in  giving  the  thalleioquin 
reaction,  and  in  the  fluorescence  of  its  solution  in  dilute  sulphuric 
acid.  It  is  distinguished  from  quinine  by  the  permanent  bulky 
precipitate  its  solutions  yield  on  successive  treatment  with  chlorine 
water,  potassium  ferricyanide,  and  ammonia ;  and  also  by  the  very 
sparing  solubility  of  its  hydriodide. 

Quinidine  Sulphate^  B2H2SO^+2H20,  crystallises  in  white 
needles  or  long  hard  prisms  which  require  about  100  parts  of  cold 
or  7  of  boiling  water  for  solution.  It  dissolves  in  7  parts  of  cold 
alcohol,  and  in  20  of  chloroform,  but  is  almost  insoluble  in  ether. 
The  salt  differs  from  the  sulphates  of  the  other  cinchona  alkaloids 
in  requiring  a  temperature  of  120°  to  render  it  anhydrous,  and  in 
readily  taking  up  the  water  again  in  moist  air. 

Quinidine  sulphate  is  an  official  remedy  in  the  United  States 
and  France.  It  is  examined  for  other  alkaloids  by  a  test  slightly 
modified  from  one  devised  by  de  Vrij  {Pharm.  Jour.,  [3],  viii. 
745),  who  utilises  the  fact  that  quinidine  hydriodide  requires  1200 
parts  of  water  for  solution.  To  test  the  purity  of  the  commercial 
sulphate  of  quinidine,  0'5  gramme  is  dissolved  in  10  c.c.  of  water 
at  60°  C,  and  an  equal  weight  of  iodide  of  potassium  free  from  any 
alkaline  reaction  added.  If  the  sample  be  pure,  hydriodide  of  quini- 
dine is  precipitated  on  stirring  and  cooling  as  a  heavy  sandy  powder, 
and  if  the  liquid  be  allowed  to  stand  for  half  an  hour  with  frequent 
agitation  and  is  then  filtered,  addition  of  one  or  two  drops  of  ammonia 
will  cause  no  turbidity  in  the  clear  filtrate.  A  slight  turbidity 
indicates  a  trifling  admixture  of  other  alkaloids,  but  if  a  decided 
precipitate  occur  the  alkaline  liquid  should  be  shaken  with  a  mixture 
of  amy  lie  alcohol  and  chloroform  (see  page  431),  or  chloroform 
only,  and  the  solvent  evaporated  to  ascertain  the  proportion  and 
nature  of  the  admixture,  which  may  be  cinchonidine  or  quinine, 
but  is  usually  cinchonine.  The  appearance  of  the  precipitated 
hydriodide  is  sufficient  indication  of  the  presence  of  impurity,  as 
in  the  presence  of  cinchonine  or  cinchonidine  it  is  resinous  instead 
of  being  sandy. 

For  the  detection  of  inorganic  impurities  {e.g.,  calcium  or  sodium 
compounds)  in   commercial  quinidine   sulphate,   Hesse   treats  one 


QUIN  AMINE.  427 

gramme  of  the  sample  with  7  c.c.  of  a  mixture  of  2  volumes  of 
chloroform  with  1  of  alcohol  of  95  per  cent.  Complete  solution 
will  take  place  in  the  absence  of  impurities. 

The  presence  of  cinchonidine  sulphate  in  the  quinidine  salt  may- 
be detected  by  treating  the  sample  with  pure  chloroform.  Unless 
only  a  very  small  proportion  of  the  impurity  be  present,  part  of  it 
will  remain  undissolved.  Smaller  quantities  may  be  detected  by 
shaking  the  chloroform  solution  with  cold  water,  in  which  the  whole 
of  the  cinchonidine  and  part  only  of  the  quinidine  salt  will  dissolve, 
and  the  former  will  be  precipitated  on  addition  of  Eochelle  salt. 

A  solution  of  quinidine  sulphate  in  chloroform  is  at  first  colour- 
less, but  on  keeping  becomes  yellow  with  a  slight  green  reflection. 

Quinamine.    CigHg^NgOg. 

This  alkaloid  was  first  discovered  by  Hesse  in  the  bark  of 
Cinchona  succwubra,  and  has  since  been  detected  in  O.  officinalis^ 
rosulenta,  and  several  varieties  of  Cinchona  Calisaya,  particularly 
Ledgeriana.^ 

Quinamine  crystallises  in  delicate  hair-like  anhydrous  needles, 
which  melt  at  172°  C.  Its  rotatory  power  in  alcoholic  solution 
is-f  104*5°  for  the  sodium  ray. 

Quinamine  is  nearly  insoluble  in  cold  water,  more  readily  in 
boiling.  Hot  alcohol  dissolves  it  freely.  It  also  dissolves  in  boil- 
ing ether,  petroleum  spirit,  and  benzene. 

Quinamine  itself  is  almost  tasteless,  but  its  solutions  in 
acids  are  very  bitter.  The  solution  in  excess  of  dilute  sulphuric 
acid  exhibits  no  fluorescence.  Acid  solutions  of  quinamine  are 
very  prone  to  decomposition  with  formation  of  an  amorphous  alka- 
loid called  quinamidine,  isomeric  with  quinamine.  Q  u  i  n- 
amicine  is  also  formed  as  a  bye-product,  and  under  certain 
conditions  apoquinamine,  C19H22N2O,  results.  When  tested 
with  chlorine  or  bromine  water  and  ammonia,  solutions  of  quina- 
mine yield  a  yellowish  amorphous  precipitate,  but  no  green  colour. 
The  solid  alkaloid,  when  moistened  with  strong  nitric  acid,  gives  a 
yellow  coloration. 

CoNQUiNAMiNE,    C^gHg^NgOg,    occurs  with    quinamine,    but    in 

1  The  motlier-liquors  from  the  crystals  of  quinine  siilphate  are  precipitated 
with  Rochelle  salt,  the  filtrate  treated  with  ammonia,  and  the  precipitate 
washed  with  ether.  The  ethereal  washings  are  treated  with  acetic  acid,  the 
liquid  neutralised,  and  while  warm  treated  with  potassium  thioeyanate,  till  on 
cooling  cinchonine  can  no  longer  be  detected.  Quinidine  is  then  precipitated, 
together  with  colouring  matter.  The  filtered  liquid  is  treated  with  soda,  and 
the  resinous  precipitate  dissolved  in  a  minimum  of  hot  80  per  cent,  alcohol, 
from  which  quinamine  crystallises  on  cooling. 


428  CONQUINAMINE. 

smaller  proportion.  It  may  be  separated  from  the  latter  base  by 
fractional  crystallisation  of  the  nitrates,  oxalates,  or  hybromides,  the 
conquinamine  salts  being  in  each  case  the  less  soluble  (An7ialen, 
ceix.  38,  62).  Conquinamine  forms  colourless  or  golden-yellow 
tetragonal  crystals,  melting  at  121°-123°,  easily  soluble  in  ether, 
chloroform,  and  benzene.  Sd  =  +  204 "1°  for  a  4  per  cent,  in  alcohol. 
M2'il2SO^-\-x  aqua  is  very  soluble.  The  aurochloride  is  a  yellow 
precipitate,  becoming  purple.  Conquinamine  closely  resembles 
quinamine.  When  heated  with  concentrated  hydrochloric  acid,  it 
yields  apoquinamine,  CigHggNgO. 

Cinchonidine.      CigHggNgO.i     (See  also  page  392.) 

This  base  is  contained  in  several  species  of  cinchona,  but  is 
especially  characteristic  of  the  red  bark  of  C.  succiruhra.  Accord- 
ing to  D.  Hooper  the  absence  of  cinchonidine  is  a  distinctive 
character  of  Remijia  barks.     It  was  formerly  called  q  u  i  n  i  d  i  n  e. 

Cinchonidine  crystallises  in  short  anhydrous  prisms  or  thin  plates, 
soluble  in  16  parts  of  alcohol  and  188  of  ether.  It  is  readily 
soluble  in  amylic  alcohol  and  chloroform.  It  is  laevo-rotatory,  Sp 
(where  c  =  4  and  ^=15°  C),  in  chloroformic  solution  being  — 70*0°; 
while  in  dilute  hydrochloric  acid  solution  (c  =  5)  Sd=  -  174"6.° 

Cinchonidine  resembles  quinine  in  the  direction  of  its  optical 
activity,  in  the  insolubility  of  the  anhydrous  neutral  sulphate  in 
chloroform,  and  in  the  sparing  solubility  of  the  tartrate  in  water. 
According  to  Hesse,  it  forms  a  crystalline  compound  with  quinine 
containing  C20H24N2O2  +  2C19H22N2O.  It  is  distinguished  from 
quinine  by  its  lesser  specific  rotation,  its  more  sparing  solubility 
in  ether,  its  non-fluorescence,  by  not  giving  the  thalleioquin 
reaction,  and  by  the  greater  solubility  of  its  neutral  and  acid 
sulphate  and  iodosulphate.  The  accurate  separation  of  cinchoni- 
dine from  quinine  presents  great  difficulties,  and  is  discussed  at 
length  on  page  411  et  seq.  Cinchonidine  has  only  about  one-fourth 
of  the  therapeutic  activity  of  quinine. 

Cinchonidine  is  isomeric  with  cinchonine,  from  which  it  differs 
by  its  Isevo-rotation ;  its  greater  solubility  in  ether ;  the  insolubility 
of  its  tartrate  in  water ;  the  insolubility  of  the  anhydrous  sulphate 
in  chloroform ;  and  the  formula  of  the  crystallised  sulphate. 

The  normal  salts  of  cinchonidine  are  neutral  to  litmus  and  methyl- 
orange,  but  acid  to  phenolphthalein.     Thus  the  precipitated  tartrate 

^  Cinchonidine  was  formcrl\'  believed  to  contain  C20H24N2O  ;  but  its  con- 
version by  heating  with  concentrated  hydrochloric  acid  into  apocinchoni- 
dine,  C19H22N2O,  without  formotion  of  methyl  chloride,  and  analyses  of 
hydrochloride,  sulpliatc,  and  chloroplatinate  establish  the  formula  given  in 
the  text. 


CINCHONIDINE  SALTS. 


429 


reacts  to  the  last  indicator  like  an  equivalent  amount  of  free  tar- 
taric acid,  and  the  combined  alkaloid  can  be  estimated  by  titration 
in  presence  of  alcohol  with  standard  caustic  soda  or  baryta. 
Adhering  Rochelle  salt  does  not  interfere. 

The  following  table  shows  the  formulae  and  solubilities  of  the 
principal  salts  of  cinchonidine  : — 


Salt. 

Formula. 

Appearance. 

Solubility  in  Water. 

Cold. 

Hot. 

Hydrochloride, 
Hydrobromide, 
Sulphate, . 

Oxalate,   .       . 
Tartrate,  . 

BHCl+laq. 
BHBr+1  aq. 
B2H2SO4+X  aq. 

B2H2C2O4+6  aq. 
B2C4HeOo+2  aq. 

Double  pyramids 
or  octahedra. 

Long  colourless 
needles. 

Silky  lustrous 
needles,  or  thin 
quadratic  prisms. 

Prismatic  crystal- 
line powder. 

Crystalline  pre- 
cipitate. 

30 
40 
100 

252  at  12° 
1265  at  10° 

Readily 
soluble. 

Freely 
soluble. 
4 

! 

... 

Cinchonidine  sulphate,  B2H2SO4,  is  remarkable  for  the  number 
of  hydrates  it  is  capable  of  forming.  From  a  moderately  con- 
centrated aqueous  solution  it  crystallises  with  6  aqua  in  brilliant 
needles ;  from  a  hot  and  concentrated  aqueous  solution  in  hard 
prisms  or  acicular  silky  crystals  containing  3  aqua  (official  in  the 
B.  and  U.S.  Pharmacopoeias)',  and  from  alcohol  in  fine  prisms 
with  2  aqua.  A  hydrate  containing  5  aqua  has  been  described 
by  Hesse. ^  The  6-atom  hydrate  is  somewhat  efflorescent.  All 
water  is  lost  at  100°,  and  2  aqua  re-absorbed  in  moist  air. 

Cinchonidine  sulphate  is  sometimes  contaminated  with  an  ad- 
mixture of  the  corresponding  salts  of  cinchonine  and  quinidine. 
To  detect  these,  Hesse  (Zeitsch.  Anal.  Chem.,  xv.  464)  dissolves 
0*5  gramme  of  the  salt  in  20  c.c.  of  water  at  60°  C,  and  adds 
1*5  gramme  of  Rochelle  salt.  A  crystalline  precipitate  of  the 
sparingly  soluble  cinchonidine  tartrate  is  produced.  After  standing 
one  hour  the  liquid  is  filtered,  and  the  filtrate  tested  with  a  drop 
of  ammonia.  Any  turbidity  or  precipitate  is  due  to  the  presence 
of  more  than  0*5  per  cent,  of  cinchonine  or  1"5  per  cent,  of 
quinidine.  These  may  be  distinguished  by  treating  the  filtrate 
with  potassium  iodide  as  described  on  pages  413  and  426. 

Hager  recommends   the   use   of  0*1   gramme  of  cinchonidine 

1  Five  commercial  samples  of  cinchonidine  sulphate  examined  by  A.  B. 
Prescott,  lost,  at  100°  C,  proportions  of  water  ranging  from  6 '36  to  7*04 
per  cent.     B2H2SO4  +  3  aqua  requires  7  '30  per  cent. 


430  HOMOCINCHONIDINE. 

sulphate,  0'3  of  Kochelle  salt,  and  20  c.c.  of  cold  water.  The 
liquid  is  frequently  agitated,  filtered  after  one  hour,  and  tested 
with  a  few  drops  of  ammonia.  As  thus  performed,  tlie  test  is 
less  strict  than  that  of  Hesse,  but  perhaps,  on  tlirit  account,  is 
better  suited  for  medicinal  purposes. 

The  precipitate  of  cinchonidine  tartrate  obtained  in  the  above 
tests  is  soluble  in  about  1200  parts  of  cold  water,  but  almost 
wholly  insoluble  in  a  strong  solution  of  Eochelle  salt.  After 
drying  at  100°  C,  it  contains  80*84  per  cent,  of  cinchonidine. 
It  will  contain  quinine  if  any  of  that  base  were  present  in  the 
sample.  In  such  case  the  solution  of  the  precipitate  in  excess  of 
dilute  sulphuric  acid  will  be  notably  fluorescent. 

Hesse  has  also  proposed  to  distinguish  the  sulphates  of  the 
cinchona  bases  by  their  behaviour  with  chloroform.  The  an- 
hydrous neutral  sulphates  of  quinine  and  cinchonidine  are  almost 
insoluble  in  alcohol-free  chloroform,  while  the  corresponding  salts 
of  cinchonine  and  quinidine  dissolve  readily  (see  pages  416,  427). 
Cinchonidine  sulphate  requires,  when  anhydrous,  300  of  boiling 
or  1000  parts  of  cold  chloroform,  the  undissolved  portion 
becoming  gelatinous.  In  the  presence  of  cinchonine  or  quinidine 
sulphate  its  solubility  in  chloroform  is  increased.  According  to 
the  British  Pharmacopoeia  (1885),  cinchonidine  sulphate  (crystal- 
lised) is  soluble  in  ether,  a  statement  which  is  misleading,  and 
correct  only  to  a  very  limited  degree.  The  U.S.  Pharmacopoeia 
describes  it  "  very  sparingly  soluble  in  ether  or  benzene." 

The  presence  of  quinidine  and  quinine  in  cinchonidine  sulphate 
can  be  recognised  by  the  thalleioquin  reaction  and  the  fluorescence 
of  the  solution  in  dilute  sulphuric  acid. 

HoMociNCHONiDiNE,  CigHggNgO  (scc  also  page  392),  accom- 
panies cinchonidine  in  many  cinchona  barks,  especially  that  of 
C.  rosulenta,  and  passes  into  the  dark  sulphate  mother-liquors  in 
the  quinine  manufacture.  It  crystallises  from  alcohol  in  anhydrous 
prisms,  or  from  a  dilute  solution  in  leaflets,  almost  insoluble  in 
water,  but  soluble  in  chloroform.  B^HgSO^  +  6Efi  crystallises 
from  hot  water  in  white  needles,  but  from  strong  solutions  the  salt 
separates  as  a  white  mass,  which  after  drying  resembles  magnesia. 

Hesse  states  that  homocinchonidine  is  an  essentially  difl'erent 
substance  from  cinchonidine,  and  that  it  is  not  possible  to  convert 
one  into  the  other.  The  two  bases  may  be  separated  by  fractional 
crystallisation  of  their  sulphates  from  aqueous  solution.  In  pre- 
sence of  quinine  sulphate,  the  homocinchonidine  salt  is  said  to 
crystallise  in  the  form  of  cinchonidine  sulphate. 

Hydrocinohonidine,  CigHg^NgO,  possibly  identical  with  c  i  n- 
chonidine,  occurs  in  the  mother-liquors  from  homocinchonidine. 


CINCHONTNE. 


4ai 


Cinchonine.      C^gH^.N.O  ;  or  C9H7N.C9Hi,(OH)N.CH3.i 

This  important  alkaloid  is  almost  invariably  present  in  cinchona 
harks.  "When  the  free  bases  are  crystallised  from  alcohol  the 
cinchonine  is  deposited  before  the  quinine  ;  unless  the  latter  base  is 
present  in  relatively  large  amount,  in  which  case  the  greater  part 
should  be  previously  removed  by  crystallising  the  sulphates. 

Cinchonine  crystallises  from  alcohol  in  anhydrous  shining  prisms 
or  needles.  It  melts  at  165°  C.  to  a  colourless  liquid,  and  par- 
tially sublimes  at  a  higher  temperature.  According  to  Hlasiwetz, 
it  may  be  readily  sublimed  in  a  current  of  hydrogen  or  ammonia. 

Cinchonine  is  almost  insoluble  in  cold  water,  and  requires  2500 
parts  of  boiling  water  for  solution. 

One  part  of  cinchonine  dissolves  in  120  parts  by  weight  of  cold 
rectified  spirit  or  28  of  boiling  alcohol,  in  350  parts  of  chloro- 
form, in  371  of  ether,  and  in  109  parts  of  amylic  alcohol.  It 
requires  only  about  13  parts  of  a  mixture  of  6  grammes  of 
chloroform  with  1  of  rectified  spirit,  and  is  soluble  in  23  parts  of 
a  mixture  of  4  of  chloroform  and  1  of  amylic  alcohol. 

A.  B.  Prescott  found  the  following  to  be  the  solubility  of 
cinchonine  in  different  physical  conditions,  and  at  the  boiling-point 
of  the  solvent : — 


Condition  of  Alkaloid. 

Parts  by  Weight  of  Washed  Solvent  required. 

Ether. 

Chloroform. 

Amylic  Alcohol. 

Benzene. 

CrystalUsed,   . 
Amorphous,    , 
"Nascent."  2.        . 

719 
563 
526 

828 
178 

22 

376 

It  will  be  seen  from  these  results  that  amylic  alcohol  is  by  far 
the  best  solvent  for  cinchonine,  except  a  mixture  of  amylic  alcohol 
and  chloroform.  On  the  other  hand,  ether  is  the  best  solvent  for 
effecting  an  approximate  separation  of  cinchonine  from  quinine. 

When  heated  to  a  high  temperature  with  an  alkali,  cinchonine 
yields  q  u  i  n  o  1  i  n  e,  CgH^N  (page  1 1 5),  together  with  other  pro- 
ducts. With  iodine  trichloride,  cinchonine  yields  a  yellow  pre- 
cipitate. 

1  The  constitution  of  cinchonine  is  discussed  on  page  168. 

*  To  obtain  the  alkaloid  in  the  "nascent"  state,  the  solvent  was  added  to 
its  sulphuric  acid  solution,  which  was  then  warmed  to  the  boiling-point  of  the 
former.  The  liquid  was  next  made  slightly  alkaline  with  ammonia,  shaken, 
kept  warm  for  five  minutes,  and  filtered. 


432  CINCHONINE  SALTS. 

Cinchonine  is  not  precipitated  in  the  cold  from  a  solution  con- 
taining tartaric  acid  by  adding  sodium  hydrogen  carbonate.  On 
heating  the  liquid,  however,  carbonic  acid  escapes  and  cinchonine 
is  separated. 

The  precipitate  formed  by  ammonia  in  solutions  of  cinchonine 
is  not  soluble  in  excess  of  the  reagent.  The  precipitate  is  amor- 
phous when  first  produced,  but  speedily  becomes  crystalline. 

Cinchonine  is  sharply  distinguished  from  quinine  by  the  very 
limited  solubility  of  the  free  base  in  ether,  by  the  solubility  of  the 
anhydrous  neutral  sulphate  in  chloroform,  by  its  failure  to  give 
the  thalleioquin  reaction,  by  its  dextro-rotatory  power,  and  by  the 
non-fluorescence  of  its  solution  in  excess  of  dilute  sulphuric  acid. 
Methods  of  detection  and  separation  based  on  these  facts  are  given 
on  pages  413  and  416. 

Cinchonine  Sulphate,  (Ci9H22N'20)2H2S04  +  SHgO,  forms  short, 
hard,  shining,  clino-rhombic  prisms,  with  dihedral  summits.  The 
salt  becomes  anhydrous  at  100°  C,  and  melts  with  partial  decom- 
position at  about  240°  C.  Cinchonine  sulphate  has  a  very  bitter 
taste,  dissolves  in  54  parts  of  cold  water,  and  is  readily  soluble 
(1:6)  in  alcohol.  It  is  insoluble  in  ether  or  benzene.  The 
anhydrous  salt  is  soluble  in  60  parts  of  cold  or  22  of  boiling 
chloroform,  a  fact  which  distinguishes  it  from  the  sulphates  of 
cinchonidine  and  quinine. 

A  solution  of  cinchonine  sulphate  does  not  give  the  thalleioquin 
reaction,  and  is  not  rendered  fluorescent  by  dilution  with  very 
weak  sulphuric  acid. 

The  mode  of  assaying  of  cinchonine  sulphate  is  sufficiently  in- 
dicated under  the  head  of  "  Quinine  Sulphate  "  (page  408  et  seq.). 

Cinchonine  Hydrochloride,  G-i^qR^2^ ^0,^.01  + 211  fi,  is  readily 
soluble  in  water  and  alcohol,  and  somewhat  so  in  ether  and  chloro- 
form. It  has  been  not  unfrequently  employed  to  adulterate 
sulphate  of  quinine.  In  such  case  the  solution  of  the  sample  in 
very  dilute  sulphuric  or  nitric  acid  will  give  a  white,  curdy  pre- 
cipitate of  silver  chloride  on  adding  silver  nitrate.  Cinchonine 
will  be  detected  by  the  tests  for  that  alkaloid. 

When  heated  in  a  dry  test-tube,  cinchonine  hydrochloride  gives 
purple  fumes  much  resembling  the  vapour  of  iodine.  The  sulphates 
of  the  cinchona  bases  do  not  give  this  reaction, 

Hydrocinchonine,  Ci9H24lSr20,  is  stated  by  H  e  s  s  e  to  occur  in 
cuprea  bark. 

CiNCHOTiNE,  C19H24N2O  (see  page  392)  is  isomeric  with  cin- 
chonamine  (page  438).  It  dissolves  very  sparingly  in  ether 
(1  :500).  BHCl  +  2  aqua  requires  about  48,  and  BgHgSO^-f  12 
aqua  about  35  parts  of  cold  water  for  solution. 


QUINOIDINE.  433 

CiNCHAMiDiNE  is  a  basG  probably  isomeric  with  the  above,  and 
identical  with  hydrocinchonidine  (page  430). 

Amorphous  Cinchona  Bases. 

Certain  uncrystallisable  alkaloids  exist  ready -formed  in  cinchona 
barks,  the  proportion  present  being  probably  affected  by  sunlight 
and  the  presence  of  any  free  acid  in  the  bark. 

In  the  preparation  of  the  salts  of  the  alkaloids  from  cinchona 
bark,  a  further  portion  of  the  bases  undergoes  conversion  into  a 
resinoid  substance  known  in  commerce  as  "  q  u  i  n  o  i  d  i  n  e  "  or 
"amorphous  quinin e." 

QuiNOfDiNB  is  obtained  in  quinine  factories  by  precipitating  the 
brown  mother-liquors  with  ammonia,  and  consists  largely  of  two 
alkaloids,  quinicine  and  cinchonicine,  which  are  isomeric 
with  and  appear  to  be  due  to  the  action  of  heat  on  quinine  or 
quinidine,  and  cinchonine  or  cinchonidine,  respectively.  These 
amorphous  products  may  also  be  obtained  by  heating  the  crystal- 
lised bases  in  glycerin  to  a  temperature  of  200°  C,  a  red  substance 
being  formed  at  the  same  time. 

Commercial  quinoidine  is  a  dark  brown,  brittle,  "  extractif orm  '^ 
mass,  softening  below  100°  C,  and  having  usually  a  slight  alkaline 
reaction.  It  is  a  product  of  indefinite  composition  which  has 
never  been  very  favourably  regarded  in  this  country,  though  it 
has  received  official  recognition  in  the  German  and  United  States 
Pharmacopoeias.  Both  works  limit  the  ash  to  0*7  per  cent.  By 
the  latter  it  is  described  as  almost  insoluble  in  water,  freely 
soluble  in  alcohol,  chloroform,  and  dilute  acids,  and  partly  soluble 
in  ether  and  benzene.  When  triturated  with  boiling  water,  the 
liquid,  after  filtration,  should  be  clear  and  colourless,  and  should 
remain  so  after  addition  of  an  alkali.  The  German  Pharmacopoeia 
requires  that  quinoidine  should  dissolve  clear  in  an  equal  weight 
of  1  part  of  dilute  acetic  acid  with  9  parts  of  water,  so  as  to 
leave  scarcely  any  residue ;  and  it  must  also  form  a  clear  solution 
with  nine  times  its  weight  of  cold  dilute  spirit.  Quinoidine  is  said 
to  be  liable  to  adulteration  with  mineral  matters,  resins,  liquorice, 
glucose,  &c.,  all  of  which  sophistications  would  be  detected  by  one 
or  other  of  the  above  tests. 

For  the  purification  of  quinoidine  it  is  recommended  to  digest 
the  commercial  article  on  the  water -bath,  with  2  parts  of 
benzene,  while  stirring  or  agitating.  The  clear  solution  is  poured 
off,  and  the  residue  washed  with  more  benzene.  The  benzene 
solution  is  then  shaken  with  a  slight  excess  of  dilute  hydrochloric 
acid,  the  acid  liquid  separated,  and  rendered  faintly  alkaline  by 
caustic  soda.     A  portion  of  this  solution  is  then  tested  for  purity 

VOL.  III.  PART  II.  2  E 


434  AMORPHOUS  CINCHONA  BASES. 

by  dilution  and  addition  of  a  few  drops  of  a  concentrated  solution 
of  sodium  thiosulphate  (hyposulphite),  which  ought  not  to  produce 
any  precipitate  insoluble  on  a  further  addition  of  water.  Should 
impurity  be  indicated,  the  whole  of  the  solution  of  quinoidine 
hydrochloride  must  be  treated  with  sodium  thiosulphate  as  long  as 
a  permanent  precipitate  is  produced.  The  liquid  is  then  filtered, 
warmed,  treated  with  excess  of  soda,  and  the  precipitated  quinoi- 
dine washed  with  water  and  dried  at  100°. 

Thus  purified,  quinoidine  appears  in  thin  layers  as  a  dark 
yellowish  brown,  transparent  mass.  It  is  completely  soluble  in 
benzene,  alcohol  and  acids,  and  ether  should  dissolve  at  least  70 
per  cent,  of  it.  The  normal  salts  of  quinoidine  are  said  to  have 
an  alkaline  reaction,  and  should  be  soluble  in  water  in  all  propor- 
tions. When  impure  they  form  a  clear  solution  in  a  little  water, 
but  the  liquid  becomes  turbid  on  further  dilution. 

To  prepare  a  pure  amorphous  alkaloid,  the  acid  sulphate  of  quinine 
or  cinchonidine,  according  to  the  product  required,  is  first  rendered 
anhydrous  by  careful  drying  at  100°  C,  and  is  then  raised  for  a 
few  minutes  to  a  temperature  of  130°  to  135°  C,  when  it  melts  and 
is  wholly  converted  into  the  acid  sulphate  of  the  new  alkaloid. 

QuiNiciNE,  C20H24N2O2,  is  a  yellowish,  amorphous,  anhydrous 
"body,  which  melts  at  about  60°  C,  assuming  a  reddish-brown 
-colour  which  becomes  darker  at  100°.  It  is  nearly  insoluble  in 
water,  but  has  a  bitter  taste.  The  alcoholic  solution  has  a  strong 
alkaline  reaction,  and  absorbs  carbon  dioxide  from  the  air.  The 
■alkaloid  is  readily  soluble  in  chloroform  or  ether.  Quinicine  gives 
3.  green  coloration  when  treated  in  solution  with  chlorine-  or 
bromine-water  and  ammonia,  but  is  distinguished  from  quinine 
and  quinidine  by  producing  a  white  amorphous  precipitate  with 
sodium  hypochlorite  or  solution  of  bleaching  powder.  In  applying 
this  test  the  liquid  should  be  slightly,  but  not  strongly,  acidulated 
with  hydrochloric  acid.  Quinicine  may  be  separated  from  the 
accompanying  alkaloids  by  adding  ammonia,  when  the  ammonium 
salt  formed  dissolves  the  liberated  alkaloid,  which  may  then  be 
recovered  by  agitation  with  ether.  If  soda  be  employed  instead 
of  ammonia  the  alkaloid  is  thrown  down  as  an  oily  mass. 

A  solution  of  quinicine  in  excess  of  dilute  sulphuric  acid  has 
a  yellow  colour  but  exhibits  no  fluorescence. 

Quinicine  forms  crystallisable  compounds  with  acids,  and  double 
salts  with  the  chlorides  of  platinum  and  gold.  Neutral  oxalate 
of  quinicine  dissolves  readily  in  hot  chloroform,  alcohol,  or  water. 
In  solution  in  a  mixture  of  alcohol  and  chloroform  the  oxalate 
exhibits  a  right-handed  rotation  corresponding  to  a  value  of 
S„  =  -I- 25-8°  for  the  alkaloid. 


AMORPHOUS   CINCHONA    BASES.  435 

Quinicine  solutions  are  not  precipitated  by  Rochelle  salt.  They 
are  completely  precipitated  by  adding  excess  of  potassium  thio- 
cyanate,  which  throws  down  quinicine  thiocyanate  as  an 
oil  which  subsequently  solidifies.  It  is  soluble  in  pure  water, 
but  insoluble  in  solutions  of  alkaline  thiocyanates. 

CiNCHONiciNE,  C19H22N2O,  when  precipitated  by  soda  from  the 
solution  of  one  of  its  salts,  forms  a  yellow  viscous  mass  readily 
drawn  out  into  colourless  strings.  It  liquefies  at  about  50°  C, 
and  at  80°  turns  brown.  At  higher  temperatures  {e.g.,  100°  C.)  it 
becomes  dark  brown,  and  is  converted  into  a  substance  resembling 
*' quinoidine."  Upon  cooling  it  remains  soft.  As  deduced  from 
the  rotatory  power  of  the  oxalate,  in  alcoholic,  aqueous,  or  chloro- 
formic  solution,  the  value  of  So  for  cinchonicine  is  +20"1°. 

In  most  reactions,  including  its  behaviour  with  ammoniacal  salts 
and  with  hypochlorites,  cinchonicine  closely  resembles  quinicine, 
and  hence  is  distinguished  from  cinchonine  and  cinchonidine. 
It  is  distinguished  from  quinicine  by  giving  no  green  colour  with 
chlorine-  or  bromine-water  and  ammonia. 

Cinchonicine  is  bitter,  and  in  the  free  state  has  a  strongly 
alkaline  reaction.  It  neutralises  acids  perfectly,  and  many  of 
the  resultant  salts  are  crystallisable. 

Anhydro-Bases.  Certain  amorphous  bases,  distinct  from  quini- 
cine and  cinchonicine,  exist  ready-formed  in  cinchona  barks.  They 
are  not  convertible  in  quinicine  or  cinchonicine,  and  appear  to 
be  formed  by  the  coalescence  of  two  molecules  of  the  crystallisable 
alkaloids,  accompanied  in  the  case  of  quinine  and  quinidine  with 
the  elimination  of  a  molecule  of  water.     Thus : — 

2C^'ii^,^fi,-^^0  =   C,„H^K,03. 

Quinine  or  Quinidine.  Diquinicine. 

Cinchonidine  or  Dicinchonicine. 

Cinchonine. 

These  bases  constitute  the  greater  part  of  the  amorphous  alkaloid 
contained  in  commercial  quinoidine.  They  are  wholly  amorphous, 
as  also  are  all  their  salts.  The  solution  of  diquinicine  in  excess 
of  dilute  sulphuric  acid  is  fluorescent,  gives  the  thalleioquin 
reaction,  and  is  dextro-rotatory.  Dicinchonicine  does  not  possess 
these  characters. 

De  Vrij  has  pointed  out  a  distinction  between  quinicine,  cin- 
chonicine, and  the  natural  amorphous  alkaloids.  If  the  neutral 
oxalates  of  the  bases  be  rendered  anhydrous  by  heating  at  100°  C, 
and  the  dry  salts  treated  with  chloroform,  they  behave  in  a 
characteristic  manner.     Oxalate   of   quinicine  dissolves   sparingly 


436  REMIJIA  ALKALOIDS. 

in  chloroform  at  the  ordinary  temperature,  but  freely  in  the 
boiling  liquid.  On  cooUng,  the  solution  deposits  the  greater  part 
oi  the  oxalate  in  crystals.  Anhydrous  oxalate  of  cinchonicine 
dissolves  freely  in  cold  chloroform.  By  adding  a  few  drops  of 
water  on  the  surface,  the  solution  is  transformed  in  a  few  minutes 
into  a  solid  mass.  The  oxalates  of  the  natural  amorphous  alkaloids 
are  very  soluble  in  chloroform.  The  solution  Temains  clear  on 
adding  a  few  drops  of  water,  but  the  water  dissolves  out  some  of 
the  oxalate  from  its  chloroformic  solution.  The  amorphous  oxalate 
is  highly  deliquescent,  but  the  oxalates  of  quinicine  and  cinchoni- 
cine remain  unchanged  in  the  air. 

Alkaloids  of  Remijia  Barks. 

The  barks  of  the  various  species  of  Remijia  vary  greatly  in  the 
alkaloids  which  they  contain.  Thus,  while  the  bark  of  R.  peduncu- 
lata  contains  quinine  and  the  allied  alkaloid  c  u  p  r  e  i  n  e,  that 
of  R.  Furdieana,  which  anatomically  closely  resembles  the  former, 
and  has  been  confounded  with  it,  contains  no  alkaloid  closely  related 
to  quinine  except  comparatively  small  proportions  (0"1  to  0*2  per 
cent.)  of  cinchonine  and  cinchonamine.  Cusconi- 
d  i  n  e,  which  occurs  in  the  bark  of  R.  Purdieana,  is  also  found  in 
that  of  Cinchona  Pelletierana,  together  with  cusconine  and 
a  r  i  c  i  n  e,  which  two  bases  do  not  appear  to  be  present  in  Remijia 
bark.  The  bases  isolated  from  this  bark  by  Hesse  were  (in 
addition  to  cinchonine  and  cinchonamine)  concusconine,  chair- 
amine,  conchairamine,  chairamidine  and  conchairamidine,  the 
formulae  and  certain  characters  of  which  are  given  on  page  393.^ 

^  To  extract  the  whole  of  the  alkaloids,  amounting  to  2  to  3  per  cent. ,  Hesse 
treated  the  finely-ground  bark  with  hot  alcohol,  distilled  off  the  solvent, 
treated  the  residue  with  excess  of  soda,  and  agitated  with  ether.  On  shaking 
the  separated  ethereal  layer  with  dilute  sulphuric  acid,  a  pale  yellow,  curdy 
mass  (A)  separated,  a  portion  of  which  remained  suspended  in  the  ether  and 
part  in  the  yellow  acid  liquid  (B).  On  separating  the  latter  (B)  and  adding 
very  dilute  nitric  acid,  cinchonamine  nitrate  was  precipitated  (mixed  with  the 
nitrates  of  some  of  the  bases  of  group  A),  while  cinchonine  remained  in  solu- 
tion. The  curdy  precipitate  (A)  was  digested  with  dilute  soda,  the  liberated 
alkaloids  washed  and  air-dried,  dissolved  in  hot  alcohol,  and  treated  with  one- 
eighth  of  their  weight  of  sulphuric  acid  (H2SO4).  Almost  all  the  concusconine 
immediately  precipitated  as  sulphate,  a  small  additional  quantity  separating  on 
cooling.  Hydrochloride  of  chairamine  was  precipitated  on  adding  strong  hydro- 
chloric acid  to  the  cold  alcoholic  mother-liquor.  The  filtrate  from  this  was 
warmed  and  treated  with  a  little  potassium  thiocyanate,  and  the  precipitate  of 
conchairamine  thiocyanate  filtered  off.  On  adding  more  of  the  reagent,  till  the 
dark  coloured  solution  became  light  brown,  a  pitchy  mass  separated,  after  the 
removal  of  which  the  solution  was  treated  with  excess  of  ammonia  and  shaken 


REMIJIA   ALKALOIDS.  437 

Concuscamidine  does  not  appear  to  be  a  definite  substance.  All 
these  alkaloids,  like  aricine  and  cusconine,  contain  four  atoms  of 
oxygen,  and  form  a  group  only  distantly  related  to  cinchonine  and 
cinchonamine.  Concusconine  has  the  same  empirical  formula  as 
cusconine,  aricine,  and  brucine,  and  resembles  the  strychnos  alka- 
loids in  some  of  its  reactions.  It  crystallises  with  1  aqua,  and  is 
dextro-rotatory,  while  cusconine  has  a  lower  melting-point,  crystal- 
lises with  4  aqua,  and  rotates  to  the  left.  Concusconine  resembles 
chairamine  and  its  isomers  in  giving  a  deep  green  coloration  when 
the  solution  in  hydrochloric  or  sulphuric  acid  is  mixed  with  con- 
centrated nitric  acid,  a  reaction  which  is  not  common  to  cusconine 
or  aricine.  Echitamine  or  ditdine,  an  alkaloid  contained  in  the 
bark  of  Alstonia  scholaris,^  only  differs  by  Hg  from  chairamine 
and  its  isomers,  to  which  it  presents  a  considerable  resemblance. 
Alstonine,  Cg^HgoNoO^,  an  amorphous  alkaloid,  which  occurs 
together  with  alstonidine  and  par pliy vine  in  the  bark  of  Alstonia 
constrida,  is  strongly  fluorescent  in  acid  solutions,  and  is  not  im- 
probably related  to  the  cusconidine  group.  Hesse  suggests  that 
gelsemine^  Cg^HggNgO^,  the  poisonous  alkaloid  from  the  root  of  Od- 
semiuni  sempervirens  (yellow  jesamine),  is  related  to  these  alka- 
loids, and  points  out  that  the  coloration  it  gives  with  nitric  acid 
somewhat  resembles  the  reaction  of  concusconine. 

with  benzene.  The  benzene  was  extracted  with  acetic  acid,  and  the  acetic 
solution  treated  with  a  saturated  solution  of  ammonium  sulphate,  which  pre- 
cipitated a  mixture  of  the  sulphates  of  chairamidine  and  conchairamidine, 
separable  by  fractional  crystallisation  from  hot  water,  in  which  the  latter  salt 
is  the  less  soluble. 

'  Dita  Bark,  from  Alstonia  or  Echites  scholaris  (Philippine  Islands),  has 
febrifuge  properties,  and  contains  the  following  alkaloids,  together  with  several 
peculiar  indifferent  bodies.  For  the  extraction  and  separation  of  the  alkaloids 
the  bark  is  extracted  with  hot  alcohol,  the  solvent  distilled  off,  the  residue 
treated  with  ammonia  and  shaken  with  ether,  which  dissolves  the  ditamine. 
Tlie  residue  is  treated  with  solid  caustic  potash  and  extracted  with  chloroform, 
which  is  evaporated,  and  the  residue  treated  with  concentrated  hydrochloric 
acid,  when  ditalne  hydrochloride  separates  while  echitenine  remains  dis- 
solved. 

DiTAiNE,  or  Echitamine,  C22H28N2O4  +  4  aqua,  forms  glassy  prisms.  Melts 
at  206°.  Sd=--28-8°.  Very  bitter.  Moderately  soluble  in  water,  alcohol, 
and  ether.  A  strong  base,  not  precipitated  by  ammonia.  Decomposes  sodium 
chloride,  setting  free  caustic  soda.  Reduces  Fehling's  solution  after  boiling 
with  hydrochloric  acid.  Concentrated  sulphuric  acid  dissolves  ditaine  with 
purple-red  colour  ;  nitric  acid  gives  a  purple-red,  changing  to  green. 

Ditamine,  CjgHjgNOg,  an  amorphous  powder  melting  at  75°,  soluble  in 
alcohol,  ether,  and  chloroform. 

Echitenine,  C20H27NO4  ;  brownish,  amorphous,  melting  above  120°.  Forms 
amorphous  salts. 


438  REMIJIA   ALKALOIDS. 

A  full  description  of  the  alkaloids  of  Remijia  Purdieana  and 
Cinchona  Pelletierana  barks  has  been  published  by  0.  Hesse 
{Annalen,  clxxxv.  296,  323;  ccxxv.  211;  Jour.  Chem.  Soc, 
xxxviii.  155  ;  xlviii.  64  ;  Pharm.  Jour.,  [3],  xv.  772).  Ar  i  c i  n e 
has  been  recently  re-investigated  by  Moissan  and  Langrin 
(Compt.  Rend.,  ex.  469).  Cinchonamine  and  cupreine  are  described 
below. 

Cinchonamine,  C19H24N2O  (see  page  393),  occurs  in  the  bark  of 
Remijia  Purdieana  (false  cuprea  bark),  a  tree  growing  in  the 
Columbian  provinces  of  Antioquia.  Its  isolation  is  described  on 
page  436.  It  is  soluble  in  alcohol,  ether,  chloroform,  benzene, 
and  carbon  disulphide,  but  only  sparingly  in  water  or  petroleum 
spirit.  It  is  very  bitter,  poisonous,^  yields  no  methyl  chloride 
when  heated  with  strong  hydrochloric  acid,  gives  no  reaction  with 
ferric  chloride,  and  no  colour  with  the  thalleioquin  test.  It  is  said 
to  be  insoluble  in  strong  hydrochloric  acid,  but  dissolves  in  strong 
nitric  acid  with  bright  yellow,  and  in  strong  sulphuric  acid  with 
reddish-yellow  colour.  BgHgSO^  forms  colourless  prisms,  readily 
soluble  in  cold  water.  BHXO3  forms  short  prisms  melting  at  195°, 
and  very  sparingly  soluble  in  cold  water  (1  :  500). 

Cupreine,  CigHggNgOg,  or  Ci9H2o(OH)N2.0H.  This  interest- 
ing alkaloid  was  discovered  by  Paul  and  Cownley  in  the  bark 
of  Cinchona  cuprea  or  Remijia  pedunculata,  a  tree  growing  in  the 
districts  surrounding  the  Magdalena  River  and  the  Upper  Orinoco. 
Since  1881,  cuprea  bark  has  been  largely  used  for  the  manu- 
facture of  quinine.^ 

Cupreine  crystallises  from  alcohol  in  the  anhydrous  form,  but 
from  ether  in  concentric  prisms  containing  2  aqua.  When  the  alco- 
holic solution  is  diluted  with  water,  the  precipitate  contains  Bg-f 
aqua.  The  hydrates  lose  their  water  at  125°.  Cupreine  is  only 
sparingly  soluble  in  ether  or  chloroform,  but  readily  in  alcohol.  The 
alcoholic  solution  is  Isevo-rotatory  (Sd=  — 175'3°),  alkaline,  gives 
a  dark  reddish  brown  coloration  with  ferric  chloride,  and  responds 
to  the  thalleioquin  test.  The  solution  of  cupreine  in  dilute  sul- 
phuric acid   is   not   fluorescent.     The    free    base   precipitated    by 

^  S60  and  Bockefontaine  {Compt.  Rend.,  c.  366)  found  cinchonamine 
(sulphate)  six  times  as  toxic  as  quinine,  cinchonidine,  or  cinchonine.  An 
injection  of  0*25  gramme  killed  a  guinea-pig  in  a  few  minutes. 

^  For  the  preparation  of  cupreine,  the  crude  quinine  sulphate  from  the 
cuprea  bark  is  dissolved  in  dilute  sulphuric  acid,  excess  of  caustic  soda  added, 
and  the  quinine  extracted  by  agitation  with  ether.  The  separated  alkaline 
liquid  is  neutralised  with  sulphuric  acid,  when  cupreine  sulphate  crystallises 
out.  The  sulphate  is  treated  with  ammonia  and  boiling  ether,  from  which 
the  cupreine  crystallises  on  cooling. 


CUPREINE.  439 

ammonia  is  only  slightly  soluble  in  excess,  and  may  be  extracted 
by  ether.  When  cupreine  is  liberated  from  a  salt  by  a  fixed 
caustic  alkali,  it  dissolves  on  adding  an  excess  of  the  reagent, 
forming  (with  soda)  a  definite  crystallisable  compound  containing 
CjgHgiNgO.ONa,  from  the  solution  of  which  the  alkaloid  cannot 
be  extracted  by  ether.-'-  This  behaviour  is  due  to  the  presence  of  a 
hydroxyl-group  having  a  phenolic  character  (compare  Morphine, 
page  311).  The  cupreinates  of  potassium  and  sodium  are 
very  soluble  in  water,  and  the  corresponding  compounds  of  calcium, 
lead,  and  silver  have  a  strong  alkaline  reaction,  and  are  more  or 
less  soluble  in  water.  From  the  fact  that  alkalies  form  only 
mono-derivatives,  while  two  atoms  of  the  hydroxyl  of  cupreine 
can  be  replaced  by  acetyl,^  it  is  probable  that  the  hydroxyl-atoms 
have  difi'erent  functions,  as  is  the  case  with  those  of  the  morphine- 
molecule. 

When  heated  with  hydrochloric  acid  (sp.  gr.  1*125)  to  140°, 
cupreine  is  converted  into  apoquinine,  without  formation  of  methyl 
chloride. 

The  conversion  of  cupreine  into  quinine  is  described  on  page  398. 

Cupreine  yields  two  classes  of  salts.  Those  of  the  general 
formula  BA  are  sparingly  soluble,  and  the  aqueous  solutions  have 
a  yellow  colour,  though  their  alcoholic  solutions  are  perfectly 
colourless.  The  salts  of  the  formula  BA2  are,  as  a  rule,  pretty 
freely  soluble,  and  their  aqueous  solutions  are  colourless. 

Cupreine  Sulphate,  B2H2SO4  +  6H2O,  crystallises  in  minute 
white  needles,  very  difficultly  soluble  in  cold  water,  and  insoluble 
in  a  saturated  solution  of  sodium  sulphate.  BHgSO^  +  HgO, 
crystallises  in  prisms  sparingly  soluble  in  cold  water.  Cupreine 
tartrate  forms  delicate  efflorescent  needles,  very  sparingly  soluble  in 
cold  water.  Cupreine  thiocyanate  is  produced  on  adding  potassium 
thiocyanate  to  a  hot  solution  of  the  monohydrochloride.  The 
liquid  becomes  turbid  and  gradually  deposits  acicular  crystals  of 
the  salt.  It  is  very  sparingly  soluble  in,  and  is  precipitated  in  an 
oily  form  by,  an  excess  of  the  precipitant. 

HoMOQUiNiNB.      When    molecular    proportions   of  quinine  and 

^  When  cupreine  and  caustic  potash  or  soda  are  mixed  in  molecular  propor- 
tions, a  portion  of  the  alkaloid  (10  to  20  per  cent.)  is  extracted  on  agitation 
•with  ether,  but  this  may  be  prevented  by  using  some  excess  of  alkali. 

2  DiACETYL-cuPREiNE,  Ci9H2o(C2H30)2N202,  was  obtained  by  Hesse  by  heat- 
ing cupreine  with  acetic  anhydride  to  85°  for  a  few  hours.  It  forms  hexa- 
gonal plates  melting  at  88°,  and  is  soluble  in  alcohol,  chloroform,  and  ether. 
The  alcoholic  solution  is  strongly  alkaline,  gives  no  colour  with  ferric  chloride, 
but  is  turned  dark  green  by  chlorine  and  ammonia.  By  caustic  alkalies,  the 
base  is  hydrolysed  in  a  few  minutes  with  formation  of  cupreine  and  acetic  acid 


440  HOMOQUININE. 

cupreine  are  dissolved  in  dilute  acid,  and  the  solution  precipitated 
by  ammonia  and  shaken  with  ether,  the  solvent  deposits  on  evapo- 
ration characteristic  crystals  ^  of  a  molecular  compound  of  quinine 
and  cupreine  containing  0301124^202,0191122^202  +  4  aqua.  The 
same  substance  is  readily  obtainable  by  precipitating  a  solution 
of  sodium  cupreinate  with  one  of  quinine  hydrochloride  : — 
C20H24N2O2, HCl  +  C19H21N2O. ONa  =  NaCl  +  C20H24N2O2,  CjaH^iNaO.  OH  . 

This  remarkable  compound  was  discovered  and  described  simul- 
taneously by  Howard  and  Hodgkin  {Jour.  Ghem.  Soc.,xli. 
66),  Paul  and  Oownley  (Pharm.  Jour.,  [3],  xii.  497),  and 
W.  G.  W h  i f  f  e n  under  the  name  of  homoquinine,  prior  to 
the  isolation  of  cupreine  by  Paul  and  Oownley  {Pharm.  Jour., 
[3],  XV.  221).  It  forms  salts,  having  different  characters  from  those 
either  of  quinine  or  cupreine,  and  is  only  resolved  into  its  consti- 
tuents by  precipitating  the  solution  with  excess  of  caustic  soda,  when 
the  quinine  may  be  shaken  out  with  ether,  while  the  cupreine 
remains  in  the  alkaline  liquid  as  sodium  cupreinate. 

The  analytical  differences  between  homoquinine  and  cupreine 
have  been  fully  described  by  Paul  and  Oownley  {Pharm, 
Jour.,  [3],  XV.  402). 

Cinchona  Barks.^ 

The  bark  of  various  species  of  Cinchona,  which,  with  about 
thirty  other  allied  genera,  constitute  the  tribe  Cinchonece  (order, 
RuMacece),  have  been  long  known  for  their  antifebrile  properties. 
These  properties  are  chiefly  due  to  peculiar  alkaloids  contained 
therein,  which  alkaloids  are  absent  from  all  the  allied  genera, 
except  certain  species  of  Remijia. 

Nearly  forty  species  of  cinchona  have  been  described,  many  of 
which  can  only  be  discriminated  with  great  difficulty.  The  cin- 
chonas form  a  very  intricate  genus,  one  series  running  into  another 
through  a  series  of  intermediate  forms,  the  number  of  which  is 
limited  to  some  extent  in  their  native  country  by  the  fact  that 
particular  species  are  practically  confined  to  certain  districts  and 
elevations. 

Only  some  seven  distinct  species  of  cinchona  yield  bark  of  any 
practical  importance.     These  are  : — 

a.  Pale  or  Crown  Bark,  yielded  by  Cinchona  officinalis  (Peru) 
and  allied  species.  It  occurs  in  quills,  with  a  rough,  blackish- 
brown  or  dark  grey  surface.      (For  analyses,  see  page  446  e^  seq.) 

^  Homoquinine  is  deposited  from  ether  in  very  thin  prismatic  laminae,  hav- 
ing  characteristically-shaped  ends  terminated  with  two  oblique  planes. 
2  French  ;  Ecorces  de  Quinquina.     German  ;  Chinxirinden. 


CINCHONA   BARKS.  441 

b.  Yellow  or  Calisaya  Bark  is,  with  tlie  exception  of  Ledger 
bark,  the  richest  of  all  the  cinchona  barks.  It  now  usually  occurs 
in  quills  having  a  rough  surface,  but  formerly  was  met  with  in 
flattened  pieces  known  as  "  flat  yellow  bark." 

c.  Red  Bark,  from  C.  rubra  and  G.  succirubra^  is  distinguished 
by  the  red  colour  of  the  sap  and  mature  bark.  It  is  extensively 
cultivated  in  India,  and  is  remarkable  for  the  large  proportion  of 
cinchonidine  contained  in  it.  (For  analyses,  see  page  446 
et  seq. 

d.  Pitayo  Bark^  from  (7.  Pitayensis,  is  imported  in  short, 
brownish,  curly  pieces,  rich  in  quinine  and  quinidine. 

e.  Columbian  and  Carthagena  Barks,  from  C.  lucumifoUa  and 
lancifoUa,  are  imported  in  soft  quills  or  broken  pieces  of  very 
variable  quality.  Quinine  is  often  wholly  absent  {Year-Book 
Pharm.,  1888,  page  425). 

/.  Ledger  Bark,  from  Cinchona  Ledger iana,  is  the  richest  in 
quinine  of  all  cinchona  barks. 

g.  Cuprea  Bark,  yielded  by  Remijia peduneulata,  is  not  a  true  cin- 
chona bark,  and  is  the  only  known  species  of  any  other  genus  which 
yields  quinine,  though  the  allied  alkaloid  cinchonamine 
(page  438)  has  been  found  in  R.  Purdieana.  Cuprea  bark  is  peculiar 
in  containing  the  interesting  alkaloid  cupreine^  (page  438). 

Hybrid  barks  are  often  produced,  especially  crosses  between  G. 
officinalis  and   C.  succirubra  (see  page  447). 

A  concise  description  of  the  chief  kinds  of  cinchona  bark,  with 
their  distinguishing  characteristics,  has  been  published  by  W. 
Elborne  (Pharm.  Jour.,  [3],  xiv.  653). 

The  British  Pharmacopoeia  of  1885  gives  the  following  as  the 
characters  of  official  (red)  cinchona  bark,  from  Cinchona  succirubra: — 

"In  quills,  or  more  or  less  incurved  pieces  coated  with  the 
periderm,  and  varying  in  length  from  usually  a  few  inches  to  a 
foot  or  more — the  bark  itself  from  about  one-tenth  to  a  quarter 
of  an  inch  thick,  or  rarely  more ;  outer  surface  more  or  less  rough 
from  longitudinal  furrows  and  ridges,  or  transverse  cracks,  annular 
fissures,  and  warts,  and  brownish  or  reddish-brown  in  colour ;  inner 
surface  brick-red  or  deep  reddish-brown,  irregularly  and  coarsely 
striated;    fracture   nearly   close    in   the   smaller   quills,   but   finely 

^  Formerly,  the  cinchona  trees  were  invariably  cut  down  and  the  bark 
stripped  oflF  and  dried  in  the  sun  or  on  hurdles  over  a  fire.  A  greatly  improved 
plan  is  to  make  longitudinal  incisions  in  the  bark  of  the  growing  tree,  remove 
about  half  the  bark,  leaving  the  remainder  intact,  and  cover  the  stem  with 
moss.  Fresh  bark  is  then  formed  very  rapidly,  and  this  renewed  bark  not 
only  contains  a  larger  percentage  of  total  alkaloids  than  the  original,  but 
the  alkaloids  contain  a  very  much  larger  proportion  of  quinine. 


442  COMPOSITION   OF   CINCHONA  BARKS. 

fibrous  in  the  larger  ones ;  powder  brownish  or  reddish-brown ;  no- 
marked  odour;  taste  bitter  and  somewhat  astringent. "^ 

The  characters  which  conventionally  determine  the  market- 
value  of  "druggists'  quills"  are  often  very  fallacious,  and  have  no- 
relation  to  the  real  quality  of  the  bark.  A  silvery  coating  on  the 
epidermis  of  the  bark  is  one  of  the  points  to  which  a  factitious 
importance  is  attached,  and  renewed  bark,  though  richer  in  alkaloid 
than  natural,  does  not  sell  readily  for  druggists'  purposes  owing  to 
the  absence  of  the  above  characters,  though  it  is  readily  bought  by 
quinine  manufacturers. 

A  specimen  supposed  to  be  one  of  cinchona  bark  can  be  readily 
identified  as  such  by  heating  a  small  quantity  in  a  test-tube,  when 
a  carmine-red  or  purple  tar  will  be  produced  if  the  sample  contain 
any  of  the  cinchona  alkaloids. 

Composition  of  Cinchona  Barks. 

Cinchona  barks  contain,  in  addition  to  woody  fibre,  starch,  gum,  and 
mineral  matters : — the  characteristic  alkaloids;  quinovin, 
and  c i n c h 0 n a-r ed;  cinchotannic  and  quinic  acids; 
colouring-matters;  wax,  fat,  and  traces  of  volatile 
oil. 

Water  extracts  only  a  portion  of  the  alkaloidal  constituents  of 
cinchona  bark,  and  a  hot  infusion  becomes  turbid  on  cooling  from 
the  separation  of  sparingly  soluble  cinchotannates  of  the  alkaloids. 
The  solution  obtained  by  treating  cinchona  bark  with  acidulated 
water  gives  a  white  precipitate  with  tannin,  a  whitish  precipitate 
with  caustic  alkalies,  and  a  yellow  crystalline  precipitate  with 
platinic  chloride.  Either  of  these  precipitates  yields  the  charac- 
teristic odour  of  quinoline  when  subjected  to  dry  distillation. 

The  Ash  of  cinchona  barks  from  South  American  sources  was 
found  by  Carles  to  contain  a  sensible  amount  of  copper,  but  this 
metal  was  not  detected  by  D.  Hooper  in  the  bark  from  trees 
cultivated  in  India  {Pharm.  Jour.,  [3],  xvii.  545),  though  in  other 
respects  the  general  results  are  in  agreement.  The  average  total 
ash  from  upwards  of  300  specimens  of  Indian  bark  was  found  by 
Hooper  to  exceed  3  per  cent.  Renewed  and  old  natural  barks 
contain  less,  but  the  proportion  never  falls  below  2  per  cent. 
Young  and  branch  barks  give  as  much  as  4  per  cent,  of  ash,  and 

^  This  description  refers  to  red  cinchona  bark  in  quills,  which,  in  the 
edition  of  1886,  replaces  the  flat  red  bark  of  South  America,  official  in  the 
Pharmaeoposia  of  1867.  The  editors  judiciously  omit  to  name  the  place  of 
origin,  whether  South  America,  Madras,  or  Ceylon;  but  they  also  omit  to 
recognise  red  bark  in  shavings,  although  this  is  the  form  in  which  it  is  so 
most  commonly  met  with  in  commerce,  and  notwithstanding  that  the  shavings 
are  often  much  superior,  as  regards  the  amount  of  quinine,  to  other  forms. 


QUINOVIN.  443 

the  leaves  from  5  to  6  per  cent.  From  24  to  27  per  cent,  of  the 
ash  is  soluble  in  water,  and  an  additional  67  to  70  per  cent,  in 
acid,  leaving  5  to  6  per  cent,  of  silica  insoluble. 

QuiNOViN,  or  Chinovin,  is  an  indifferent  body  which  appears  to 
be  a  constant  constituent  of  the  cinchonas,  but  in  a  proportion 
seldom  exceeding  2  per  cent.  It  is  dissolved  on  treating  the  bark 
with  weak  soda,  and  on  adding  hydrochloric  acid  to  the  solution  is 
precipitated  in  admixture  with  quinovic  acid  and  cinchona-red. 
Treatment  with  milk  of  lime  dissolves  the  quinovin  and  quinovic 
acid,  which  are  reprecipitated  by  an  acid  and  separated  by  treat- 
ment with  chloroform,  which  dissolves  the  quinovin  only.^ 

Quinovin  has  recently  been  re-investigated  by  Liebermann 
and  Giesel  {Berichte,  xvi.  987;  Pharm.  Jour.^  [3],  xvi.  987), 
who  ascribe  to  it  the  formula  ^^^^'f^w  They  believe  two 
distinct  modifications  to  exist,  a-quinovin  being  present  in 
cinchona  bark  and  /S-quinovin  in  cuprea  bark,  a-quinovin  is 
a  white,  very  light,  crystalline  powder,  quite  insoluble  in  cold  and 
almost  insoluble  in  hot  water,  but  soluble  in  cold  caustic  alkalies, 
lime  and  baryta  water,  and  ammonia.  It  is  difficultly  soluble  in 
chloroform,  ether,  and  benzene.  It  dissolves  in  nearly  absolute 
alcohol  (43  :  100  at  15°),  and  is  obtained  on  evaporation  over 
sulphuric  acid  as  a  gummy  mass  without  any  tendency  to 
crystallisation;  but  it  separates  on  diluting  the  solution  with 
water  in  rosettes  of  clear,  very  small  needles.  When  precipi- 
tated by  treating  its  solution  in  more  dilute  alcohol  with  water 
it  is  deposited  in  glittering  white  scales.  The  alcoholic  solution 
of  quinovin  is  dextro-rotatory  (S=-f56'6),  does  not  reduce 
Fehling's  solution,  and  does  not  undergo  fermentation  with  yeast. 
The  powder  is  very  bitter.  In  concentrated  sulphuric  acid  it 
dissolves  with  orange-yellow  colour  and  evolution  of  carbon  mon- 
oxide. Its  solution  in  glacial  acetic  acid  is  faintly  blue,  as  is 
also  the  precipitate  thrown  down  on  diluting  the  solution  with 
water. 

^-quinovin  closely  resembles  its  isomer,  but  is  not  soluble  in 

*  Quinovin  is  prepared  by  Liebermann  and  Giesel  from  a  bye-product 
obtained  when  the  cinchona  bases  are  extracted  from  bark  by  means  of  alcohol. 
On  distiUing  off  the  alcohol,  and  treating  the  extract  with  a  dilute  mineral  acid, 
the  alkaloids  are  dissolved  as  salts.  The  insoluble  brown  resinous  matter  is 
digested  with  warm  milk  of  lime,  and  the  filtered  liquid  precipitated  by 
liydrochloric  acid.  The  precipitate  is  dried  and  digested  with  alcohol,  which 
leaves  a  little  quinovic  acid  undissolved  as  a  white  powder.  The  brown 
solution  is  diluted  with  water  till  a  precipitate  commences  to  form,  when 
small  crystals  of  quinovin  separate  on  standing.  By  recry stall isation  from 
dilute  alcohol  it  is  obtained  pure  in  the  form  of  small  glittering  scales. 


444  QUINOVIC   ACID. 

absolute  ether  or  ethyl  acetate,  and  crystallises  readily  from  dilute 
alcohol  in  handsome  scales.  In  nearly  absolute  alcohol  it  dissolves 
freely  with  slight  evolution  of  heat,  but  after  a  time,  even  if 
evaporation  be  prevented,  the  greater  part  separates  in  glassy 
crystals  containing  C^^liQ2p-^-^^  + 5C2iiQOj  which  effloresce  very 
rapidly  in  the  air  with  loss  of  the  alcohol.  The  specific  rotation 
of  /5-quinovin  is  +27*9°. 

When  boiled  for  some  time  with  dilute  sulphuric  acid,  or, 
preferably,  when  their  concentrated  alcoholic  solutions  are  saturated 
with  hydrochloric  acid  gas  and  allowed  to  stand  in  a  closed  vessel 
for  thirty  hours,  both  the  quinovins  undergo  complete  decom- 
position into  quinovic  acid  and  quinovit,  a  saccharoid 
body  apparently  containing  CgH-^2^4-  This  substance  is  very  hygro- 
scopic, and  has  not  been  ol^tained  crystalline,  but  may  be  distilled 
unchanged  in  small  quantities,  has  a  sweet  taste  with  a  bitter 
after-taste,  is  dextro-rotatory,  and  does  not  reduce  Fehling's 
solution  even  after  boiling  with  acid.  It  is  doubtful  if  quinovit 
has  been  obtained  pure. 

Quinovic  Acid,  CggH^gOg,  is  constantly  present  in  cinchona  barks 
in  small  proportion,  and  forms  a  snow-white  powder  of  tasteless 
needles  or  scales,  quite  insoluble  in  water,  ether,  or  chloroform, 
and  only  very  sparingly  soluble  in  boiling  alcohol  or  glacial  acetic 
acid.  It  is  best  dissolved  by  adding  ammonia  to  the  alcohol,  and 
may  be  reprecipitated  by  acetic  acid.  Quinovic  acid  decomposes 
carbonates,  and  is  soluble  in  ammonia  and  solutions  of  the  caustic 
alkalies  and  alkaline  earths,  the  solutions  frothing  like  soap.  The 
ammonium  and  calcium  salts  crystallise  from  alcohol  in  needles ; 
the  former  salt  losing  its  ammonia  by  exposure  to  air,  or  on  boiling 
its  solution.  On  adding  an  acid  to  an  alkaline  solution  of  quinovic 
acid,  a  hydrate  of  quinovic  acid  is  thrown  down  as  a  very  voluminous 
jelly,  the  whole  contents  of  the  vessel  solidifying.  In  this  form 
quinovic  acid  is  very  soluble  in  ether  and  alcohol.  From  the 
solution,  the  insoluble  form  of  the  acid  separates  in  needles  on 
standing.  Quinovic  acid  gives  with  cupric  sulphate  first  a 
green  colour  and  then  a  precipitate,  and  the  latter,  when  washed, 
has  a  bitter  metallic  taste.  When  heated  to  about  300°  C,  quinovic 
acid  yields  pyroquinovic  acid,  carbon  dioxide,  and 
secondary  products. 

CiNCHOTANNiN  or  CiNCHOTANNic  AciD,  Ci^HjgOg,  is  a  glucosidc 
which  is  an  important  constituent  of  cinchona  barks,  in  which  it 
exists  in  the  proportion  of  3  to  4  per  cent.  It  may  be  precipitated 
IS  a  lead  salt  from  a  decoction  of  bark — previously  treated  with 
magnesia  to  separate  colouring-matter — by  addition  of  lead  acetate. 
The  yellow  precipitate  when  decomposed  by  sulphuretted  hydrogen 


CINCHONA   BARKS.  445 

yields  a  solution  of  cinchotannic  acid.  It  is  a  yellow,  amorphous, 
very  hygroscopic  substance,  very  soluble  in  water,  alcohol,  and 
ether ;  gives  a  green  colour  with  ferric  chloride ;  is  precipitated 
by  starch,  albumin,  gelatin,  and  tartar-emetic;  is  hydrolysed  by 
dilute  acids  into  glucose  and  c  i  n  c  h  o  n  a-r  e  d ;  gives  p  r  o  t  o- 
catechuic  and  acetic  acids  on  fusion  with  caustic  potash ; 
yields  pyrocatechol  on  dry  distillation ;  and  is  readily 
decomposed  in  presence  of  excess  of  alkalies,  with  formation  of 
cinchona-red.  The  cinchotannates  of  the  alkaloids  existing 
naturally  in  cinchona  bark  are  difficultly  soluble  in  water,  but 
dissolve  readily  in  acidulated  water — probably  with  decomposition. 

Cinchona-red  or  Cinchofulvic  Acid,  C12H14O7.  This  is  the 
natural  colouring-matter  of  (red)  cinchona  barks,  from  which  it 
may  be  extracted  by  treatment  with  alkalies.  It  is  re-precipi- 
tated from  its  red  ammoniacal  solution  on  addition  of  hydrochloric 
acid.  The  solution  also  yields  a  red  precipitate  with  barium 
chloride.  Cinchona-red  is  also  produced  by  boiling  cinchotannic 
acid  with  dilute  sulphuric  acid,  glucose  being  simultaneously 
formed.  On  fusing  cinchona-red  with  potash,  protocatechuie 
acid,  Ci^HgO^,  is  produced.  Cinchona-red  is  insoluble  in  water 
or  ether,  but  sparingly  soluble  in  alcohol.  It  is  sometimes  present 
in  red  bark  to  the  extent  of  10  per  cent. 

QuiNic  Acid  or  Kinic  Acid,  CyH^gOg,  crystallises  in  well- 
defined  hexagonal  plates,  fusing  at  161°  C.  It  has  a  strong  and 
purely  acid  taste,  and  is  soluble  in  2  parts  of  water,  less  soluble 
in  alcohol,  and  almost  insoluble  in  ether.  Its  solutions  are  Isevo- 
rotatory.  When  distilled  with  manganese  dioxide  and  sulphuric 
acid,  kinic  acid  yields  quinone,  C^^H^Og,  which  is  deposited 
in  deep  yellow  prisms  on  the  cooler  part  of  the  apparatus.  This 
reaction  was  proposed  by  Stenhouse  as  a  test  for  true  cinchona 
hark. 

The  Alkaloids  are  the  most  important  constituents  of  cinchona 
barks,  in  which  they  exist  in  the  form  of  cinchotannates  and  quinates. 
The  principal  of  them  have  already  been  fully  described  (page  398 
et  seq.).  The  official  tincture  and  liquid  extract  of  cinchona  contain 
only  a  portion  of  the  alkaloids  of  the  bark  used  for  their  preparation 
{Pharm.  Jour.,  [3],  xiv.  445,  797  ;  xv.  453,  480). 

Some  kinds  of  cinchona  bark  are  occasionally  wholly  destitute 
of  alkaloids.  Such  specimens  do  not  give  a  carmine-red  tar  when 
heated  in  a  dry  tube,  this  reaction  being  produced  only  when  a 
cinchona  base  is  heated  with  woody  fibre. 

The  proportions  of  total  alkaloids,  as  also  the  percentage  of 
quinine,  are  extremely  variable  (see  Pharm.  Jour.,  [3],  xiv.  444, 
445,  458,  797,  810;  xv.  411,   453,  480),  and  chemical  analysis 


446 


COMPOSITION   OF   CINCHONA   BARKS. 


is  the  only  means  of  forming  an  opinion  as  to  the  richness  of  a 
specimen  of  bark.  De  Yrij  found  the  G.  officinalis  grown  at 
Ootacamund  to  contain  a  proportion  of  total  alkaloids  varying  from 
11-96  per  cent,  (of  which  9'1  per  cent,  was  quinine)  down  to  less 
than  1  per  cent.  Quinine  is  not  seldom  absent  from  barks  con- 
taining certain  other  of  the  cinchona  alkaloids.  The  highest  yield 
of  total  alkaloid  known  is  about  15  per  cent.  An  Ootacamund 
bark  has  been  found  to  contain  13  J  per  cent.,  the  greater  part 
being  quinine.  In  eighty  specimens  of  Calisaya  Ledgeriana,  from 
Java,  Moens  in  1879  found  from  12*50  to  1*09  per  cent,  of  total 
alkaloids,  the  quinine  ranging  from  11*6  to  0'8  percent. 

Of  late  years,  owing  to  improved  methods  of  cultivation,  the 
proportion  of  quinine  has  sensibly  increased.  In  the  same  species 
of  cinchona,  the  natural  bark,  mossed  bark,  and  renewed  bark  con- 
tain very  different  percentages  of  quinine,  the  last  being  the  richest ; 
besides  which  the  external  conditions  under  which  the  trees  are 
grown  largely  affect  the  relative  and  absolute  proportions  of  the 
alkaloids  in  the  bark. 

Quinine  and  cinchonine  are  the  cinchona  alkaloids  of  the  most 
frequent  occurrence.  Cinchonidine  is  hardly  less  common,  and  it 
occurs  very  largely  in  Indian  red  bark.  Quinidine  is  not  very 
frequent,  and  is  never  present  in  large  amount. 

The  following  are  analyses  by  D.  Howard  of  bark  from 
cultivated  cinchona  trees  grown  near  Bagota,  United  States  of 
Columbia  (New  Granada).  The  characters  of  the  barks  have  been 
described  by  E.  M.  Holmes  {Phai-m.  Jour.,  [3],  xxii.  875). 


Species  of  Cinchona. 

6 

'3 

h 

1 

6 

a 

1 

f§ 

li 

^ 

S^ 

1 

a 

g  o 

H:3 
< 

Tliomsoniana, 

5-94 

4-45 

0-27 

0-26 

0-82 

0-74 

6-54 

Ledgeriana  verde, 

5-90 

3-68 

0-00 

0-20 

0-01 

0-44 

4-33 

Morada,  '.'.'.'. 

7-30 

5-48 

0-00 

trace 

0-10 

0-78 

6-26 

306 

2-30 

000 

0-50 

0-04 

0-38 

3-22 

Tuna, 

904 

6-78 

0  40 

018 

0-38 

0-42 

8-16 

Pombiana, 

6-88 

4-41 

0-34 

trace 

0-02 

0-26 

5-03 

Officinalis, 

6-32 

4-74 

1-23 

0-07 

0-10 

0-42 

6-66 

Succirubra ,'   . 

5-93 

4-45 

2-77 

0-02 

0-12 

0-36 

7-72 

Hybrid,    . 

3-32 

2-49 

1-92 

trace 

0-04 

0-52 

4-97 

This  is  by  no  means  a  typical  analysis  of  succirubra  bark  (see  footnote,  page  447). 


The  following  are  analyses  by  D.  Hooper,  Government 
Quinologist,  of  cinchona  barks  grown  in  the  Madras  Govern- 
ment plantations,  and  shown  at  the  Indo-Colonial  Exhibition  in 
1886:— 


ALKALOIDS   OF   CINCHONA    BAKKS. 


4.47 


Source  of  Bark. 

•It 

6 

a 
"a 

I 

i 
1 

<6 

a 

a 
o 

ll 

1^ 

Species. 

Description. 

C.  succirubra,  . 

Natural 

2-57 

1-91 

1-14 

... 

2-11 

0-88 

6-04 

i» 

Mossed 

2-27 

1-69 

1-68 

... 

2-03 

0-98 

6-34 

>t 

Renewed 

2-47 

1-84 

1-25 

... 

1-48 

0-71 

5-28 

»»             •        • 

Branch 

1-85 

1-38 

1-59 

2-28 

1-16 

6-41 

Root 

1-66 

1-24 

1-43 

0-41 

0-77 

1-27 

5  12 

>> 

Renewed  (shavings) 

3-09 

2-30 

2-06 

1-16 

1-45 

6-97 

C.  robusta,^ 

Natural 

1-92 

1-43 

1-58 

... 

2-08 

0-31 

5-40 

»i             • 

Mossed 

2-58 

1-92 

0-77 

3-16 

0-35 

6-20 

»> 

Renewed 

5-92 

4-40 

0-51 

... 

2-54 

1-65 

910 

M 

Branch 

2-20 

1-64 

1-17 

2-71 

0-50 

602 

C.  micrantha,  . 

Natural 

... 

1-92 

0-40 

2-32 

>• 

Renewed 

trace 

trace 

1-12 

... 

2-45 

1-02 

4-54 

>> 

Branch 

1-60 

0-45 

2-05 

C.  Calisaya,     . 

Natural 

1-62 

1-21 

2  13 

... 

2-32 

0-29 

5-95 

„ 

Branch 

0-79 

0-59 

1-93 

073 

0-48 

3-73 

C.  Angliea,^     .       . 

Natural 

1-09 

0-81 

1-49 

0-29 

0-88 

0-44 

3-91 

«>             • 

Branch 

trace 

trace 

2-04 

0-25 

... 

0-36 

2-65 

C.  Ledgeriana, 

Natural 

7-38 

5-49 

0-82 

... 

1-33 

0-88 

8-52 

» 

Branch 

2-97 

2-21 

107 

0-49 

0-50 

4-27 

C.  Javaniea,    . 

Natural 

... 

2-64 

1-32 

... 

0-48 

4-44 

„ 

Branch 

... 

1-49 

1-43 

... 

0-45 

3-37 

C.  offieinalis,    . 

Natural 

3-72 

2-77 

0-39 

0-16 

1-57 

0-50 

5-39 

» 

Mossed 

4-57 

3-40 

0-45 

0-20 

1-50 

0-62 

617 

,,             .       , 

Renewed 

5-66 

4-21 

0-65 

0-22 

0-85 

0-70 

6-63 

C.  paludiana,  . 

Natural 

0-05 

0-04 

0-39 

... 

0  10 

0-43 

0-96 

»> 

Renewed 

0-68 

0-51 

0-28 

... 

1-19 

0-87 

2-85 

C.  Pitayensis, .       . 

Natural 

3  14 

2-34 

1-93 

1-10 

0-56 

0-39 

6-32 

If 

Mossed 

5-12 

3-81 

1-91 

0-63 

0-95 

0-37 

7-67 

„ 

Renewed 

3-36 

2-50 

2-33 

0-78 

0-52 

0-55 

6-68 

C.  Humbolticma,     . 

Natural 

3-01 

2-24 

0-49 

trace 

1-55 

0-90 

5-18 

»» 

Renewed 

1-72 

1-28 

0-43 

0-64 

107 

3-42 

»  CiTichona  robusta  is  a  hybrid  or  cross  between  C.  sticcirubra  and  C.  officinalis,  and 

C.  Anglica  between  C.  succirubra  and  C.  Calisaya  (W.  T.  Thiselton  Dyer,  Pharm. 
Jour.,  [3],  XV.  481). 

Analyses  of  a  number  of  cinchona  barks  from  Madras  have 
been  published  by  B.   H.   Paul  {Pharm.  Jour.,  [3],  xiv.  QQQ). 

D.  Hooper  (Year-Book  Pharm.,  1888,  page  430)  gives  the 
following  as  the  percentage  proportions  of  alkaloids  in  typical 
barks  from  trees  grown  on  the  plantations  of  the  Madras  Govern- 
ment :  ^ — 

^  In  commenting  on  these  results,   B.   H.   Paul  strongly  deprecated  the 
preference  given  to  the  red  bark  over  that  of  the  crown  and  Calisaya  barks, 


448 


COMPOSITION   OF   CINCHONA    BARKS. 


Bark  from 
C.  succirubra.^ 

Crown  Bark  from 
C.  officinalis.^ 

Hybrid 
Barks. 

Quinine 

Cinchonidine, 
Quinidine, 
Cinchonine, 
Amorphous  alkaloids,  . 

1-40 
2-25 

1-92 
0-68 

2-98 
1-40 
0-08 
0-42 
0-42 

2-16 
1-82 
0  04 
117 
0-56 

Total, 

6-25 

5-25 

5-75 

Hooper  gives  the  following  as  the  average  centesimal  com- 
position of  the  alkaloids  from  numerous  species  of  the  above 
barks : ^ — 


Red  Barks.2 

Crown  Barks. 

Hybrid  Barks. 

Quinine, 

Cinchonidine,        

Quinidine,     .... 
Cinchonine,    . 
Amorphous  alkaloids,  . 

22-2 
361 

30-9 

10-8 

55-9 

26-7 

1-5 

8-0 

7-9 

41-2 

40-9 

0-5 

9-7 

7-7 

Total, 

100-0 

100-0 

100-0 

which  had  acted  prejudicially  on  all  concerned.  This  prejudice  had  extended 
to  the  B.  Pharmacopoeia,  with  the  result  that  "every  bark  preparation  that 
appeared  there  was,  in  fact,  an  officially  adulterated  article,"  and  contained  for 
every  unit  of  quinine,  the  only  really  valuable  constituent,  2,  3,  or  4  per  cent, 
of  the  comparatively  valueless  ones  ( Year-Book  Pharrti.,  1888,  page  440).  The 
typical  crown  bark,  of  which  the  analysis  is  given  in  the  text,  Paul  regarded  as 
of  only  inferior  quality,  the  proportion  of  alkaloids  yielded  by  crown  bark  of 
any  value  being  from  3  to  5  per  cent,  of  sulphate  of  quinine,  and  something 
less  than  1  per  cent,  of  cinchonidine.  In  the  red  bark  these  proportions  were 
reversed,  the  quinine  being  usually  1^  per  cent.,  with  3,  4,  and  5  per  cent,  of 
cinchonidine.  Red  bark  had  become  a  drug  in  the  market,  and  almost  worthless 
as  a  source  of  quinine.  In  replying  to  these  criticisms  {Pharm.  Jour.,  [3], 
xix.  504),  Hooper  pointed  out  that  the  fifty  crown  barks  of  which  the  analyses 
were  given  were  undoubtedly  of  a  typical  character  ;  barks  of  the  richer  species, 
as  angustifoUa,  were  purposely  omitted  ;  and  that  mossed  and  renewed  barks 
are  also  eliminated. 

^  See  foregoing  footnote. 

^  The  mixed  total  alkaloids  of  red  bark  have  been  introduced  into  commerce 
under  the  name  of  "  Q  u  i  n  e  t  u  m. "  This  preparation  is  completely  soluble  in 
warm,  strong  alcohol ;  3'1  grammes  dissolved  in  10  c.c.  of  normal  hydrochloric 


CINCHONA   BARKS.  449 

Assay  of  Cinchona  Barks. 

The  complete  assay  of  the  various  species  of  cinchona  bark,  with 
the  view  of  ascertaining  the  proportion  of  the  different  alkaloids 
contained  in  them,  is  a  process  at  once  important  and  difficult.  A 
great  many  methods  have  been  proposed,  but  very  few  can  be 
trusted  to  yield  accurate  results  when  employed  by  chemists  unused 
to  them.  Again,  a  process  which  is  suitable  when  quinine  is  the 
chief  alkaloid  present  becomes  difficult  of  application  when  the 
cinchonidine  is  in  excess.  Unfortunately,  also,  certain  processes 
which  are  extensively  employed  by  professed  quinologists  are  kept 
strictly  secret. 

In  choosing  a  process  of  assaying  cinchona  bark,  due  considera- 
tion should  be  given  to  the  kind  of  information  required.  Thus, 
a  pharmacist  desiring  to  know  the  alkaloidal  strength  of  his  bark 
will  require  a  less  accurate  and  elaborate  process  than  a  manufacturer 
buying  bark  for  the  extraction  of  quinine.  Again,  in  some  cases 
it  is  sufficient  to  determine  the  percentage  of  total  alkaloids,  while 
in  others  it  is  very  important  to  ascertain  the  proportion  of  crystal- 
lised sulphate  of  quinine  which  the  bark  is  capable  of  yielding. 
On  this  account,  it  is  desirable  to  discuss  the  determination  of  the 
total  alkaloids  and  of  the  actual  quinine  separately. 

a.  The  British  Pharmacopoeia  of  1885  prescribes  the  following 
standard  of  quality  and  method  of  assaying  ^  red  cinchona  bark  : — 

"  Test. — When  used  for  purposes  other  than  that  of  obtaining 
the  alkaloids  or  their  salts,  it  should  yield  between  5  and  6 
per  cent,  of  total  alkaloids,  of  which  not  less  than  half  shall 
consist  of  quinine  and  cinchonidine,^  as  estimated  by  the  following 
methods : — 

"1.  For  Quinine  and  Cinchonidine. — Mix  200  grains  of  red 
cinchona  bark,  in  No.   60  powder,  with  60  grains  of  hydrate  of 

acid  should  give  a  clear  solution,  which,  on  addition  of  2  grammes  of  Rochelle 
salt  must  yield  a  precipitate  equal  in  weight,  after  drying,  to  at  least  65  per 
cent,  of  the  quinetum  taken. — (From  the  Unofficial  Formulary  of  the  Dutch 
Society  for  the  Advancement  of  Pharmacy,  Pharm.  Jour.,  [3],  xii.  662.) 
"  Quinetum  sulphate  "  occurs  in  commerce  in  a  perfectly  crystallised  form. 

^  Based  on  a  method  devised  by  E.  R.  Squibb  {Ephemeris,  i.  106). 

2  This  is  not  a  veiy  exacting  requirement.  Unfortunately  no  indication  is 
given  of  the  proportion  of  actual  quinine  which  should  be  present.  Con- 
sequently, one  bark  may  have  double  the  intrinsic  value  of  another,  and  yet 
both  be  fairly  up  to  the  B.P.  standard.  It  is  quite  possible  for  a  bark  to 
contain  the  required  proportion  of  total  alkaloid,  of  which  one-half  shall 
consist  of  cinchonidine  and  quinine,  but  still  only  traces  of  the  last  alkaloid 
to  be  present.  As  the  shavings  are  excluded,  and  the  established  prejudice 
as  to  the  appearance  of  quills  tends  to  favour  the  use  of  natural  rather  than 
the  richer  renewed  bark,  the  general  effect  is  to  promote  the  use  of  the  least 

VOL.   III.  PART  II.  2   F 


450  B.P.   METHOD   OF  ASSAYING   CINCHONAS. 

calcmm;  slightly  moisten  the  powders  with  half  an  ounce  of 
water  ;  mix  the  whole  intimately  in  a  small  porcelain  dish  or 
mortar ;  allow  the  mixture  to  stand  for  an  hour  or  two,  when  it 
will  present  the  characters  of  a  moist,  dark  brown  powder,  in  which 
there  should  be  no  lumps  or  visible  white  particles.  Transfer 
this  powder  to  a  six-ounce  flask,  add  three  fluid  ounces  of  benzolated 
amylic  alcohol,^  boil  them  together  for  about  half  an  hour,  decant 
and  drain  off"  the  liquid  on  to  a  Alter,  leaving  the  powder  in  the 
flask ;  add  more  of  the  benzolated  amylic  alcohol  to  the  powder, 
and  boil  and  decant  as  before ;  repeat  this  operation  a  third  time ; 
then  turn  the  contents  of  the  flask  on  to  the  filter,  and  wash  by 
percolation  with  more  of  the  benzolated  amylic  alcohol  until  the 
bark  is  exhausted.  If,  during  the  boiling,  a  funnel  be  placed  in 
the  mouth  of  the  flask,  and  another  flask  filled  with  cold  water 
be  placed  in  the  funnel,  this  will  form  a  convenient  condenser 
which  will  prevent  the  loss  of  more  than  a  small  quantity  of  the 
boiling  liquid.  Introduce  the  collected  filtrate,  while  still  warm, 
into  a  stoppered  glass  separator ,  add  to  it  20  minims  of  diluted 
hydrochloric  acid,  mixed  with  2  fluid  drachms  of  water;  shake 
them  well  together,  and  when  the  acid  liquid  has  separated 
this  may  be  drawn  off",  and  the  process  repeated  with  distilled 
water  slightly  acidulated  with  hydrochloric  acid,  until  the  whole 
of  the  alkaloids  have  been  removed.  The  acid  liquid  thus  obtained 
will  contain  the  alkaloids  as  hydrochlorates,  with  excess  of  hydro- 
chloric acid.  It  is  to  be  carefully  and  exactly  neutralised  with  am- 
monia while  warm,  and  then  concentrated  to  the  bulk  of  3  fluid 
drachms.  If  now  about  15  grains  of  tartarated  soda,  dissolved 
in  twice  its  weight  of  water,  be  added  to  the  neutral  hydro- 
chlorates,  and  the  mixture  stirred  with  a  glass  rod,  insoluble  tartrates 
of  quinine  and  cinchonidine  will  separate  completely  in  about  an 
hour ;  and  these  collected  on  a  filter,  washed,  and  dried,  will  contain 
eight-tenths  of  their  weight  of  the  alkaloids,  quinine  and  cinchoni- 
dine, which,  divided  by  2,  represents  the  percentage  of  those  alka- 
loids.    The  other  alkaloids  will  be  left  in  the  mother-liquor." 

"2.  For  Total  Alkaloids. — To  the  mother-liquor  from  the  pre- 
ceding process  add  solution  of  ammonia  in  slight  excess.  Collect, 
wash,  and  dry  the  precipitate,^  which  will  contain  the  other 
alkaloids.     The    weight    of    this    precipitate,    divided    by    2    and 

valuable  kinds  of  bark  for  pliarniaceutical  purposes.  In  the  present  Pharma- 
copoeia definition,  the  quinine  standard  of  cinchona  bark  is  reduced  much 
below  that  of  the  1867  edition,  and  only  corresponds  to  a  content  of  about 
1  per  cent,  of  quinine. 

1  Prepared  by  mixing  3  volumes  of  benzene  with  1  of  amj'lic  alcohol. 

■■^  It  would  be  better  to  extract  the  alkaloids  with  chloroform. 


ASSAY   OF   CINCHONA   BARKS.  451 

added  to  the  percentage  weight  of  the  quinine  and  cinchonidine, 
gives  the  percentage  of  total  alkaloids." 

h.  The  following  method  of  determining  the  total  alkaloids  of 
cinchona  bark  is  that  of  J.  E.  D  e  Y  r  i  j,  with  certain  modifications 
suggested  by  A.  B.  P  r  e  s  c  o  1 1  and  J.  M  u  t  e  r.  It  is  [)ractically 
the  official  process  of  the  United  States  Pharmacopoeia,  and  is 
applicable  to  all  varieties  of  bark.  Twenty  grammes  of  the  finely- 
powdered  bark,  weighed  after  drying  at  100°  C,  is  thoroughly 
mixed  with  5  grammes  of  quick-lime  and  50  c.c.  of  water.  The 
mixture  is  then  dried  at  a  very  gentle  heat,  not  above  70°  to 
80°  C.  When  dry,  it  is  transferred  to  a  flask  fitted  with  an 
inverted  condenser,  and  boiled  with  200  c.c.  of  the  strongest 
rectified  spirit.^  The  liquid  is  allowed  to  cool,  and  is  then  passed 
through  a  filter  six  inches  in  diameter,  and  the  residue  is  again 
boiled  with  100  c.c.  of  alcohol,  and  then  washed  twice  with 
alcohol,  using  50  c.c.  each  time.  The  filtrate  is  next  rendered 
slightly  acid  by  dilute  sulphuric  acid,  and,  after  allowing  any 
precipitate  of  calcium  sulphate  to  subside,  the  liquid  is  passed 
through  a  very  small  filter,  which  is  washed  with  a  little  alcohol. 
The  filtrate  is  evaporated  or  distilled  till  the  alcohol  is  expelled, 
cooled,  and  again  passed  through  a  small  filter,  the  precipitate, 
consisting  of  quinovic  acid  and  fatty  matter,  being  washed  with 
water  slightly  acidulated  with  sulphuric  acid.  The  filtrate,  which 
contains  the  alkaloids  in  the  form  of  acid  sulphates,  is  then  con- 
centrated to  about  50  c.c.  or  less,  and  transferred  to  a  separator 
of  100  to  150  C.C.  capacity.  Soda  is  next  added  in  decided 
excess,  and  the  liquid  containing  the  separated  alkaloids  then 
shaken  without  delay  with  30  to  40  c.c.  of  previously  washed 
chloroform.  After  a  few  minutes'  agitation,  the  liquid  is  left  at 
rest  till  the  chloroform  has  completely  separated  from  the  aqueous 
layer.  The  lower  stratum  is  .then  tapped  off",  and  the  watery 
liquid  agitated  three  times  more  with  chloroform,  using  from 
25  to  30  c.c.  on  each  occasion.  The  mixed  chloroformic  solu- 
tions are  then  distilled  to  a  small  bulk,  the  residual  liquid 
evaporated  to  dryness,  and  the  residue  dried  in  the  water-oven 
till  constant  in  weight.  The  amount  so  found  represents  the 
total  alkaloids  in  the  20  grammes  of  the  bark  taken.  Cinchonine 
and  cinchonidine  readily  become  anhydrous  at  100°,  and  quinine 
may  be  trusted  to  do  the  same.  Quinidine  retains  2  aqua  in  the 
water-oven,  but  the  proportion  in  which  this  base  occurs   is  too 

^  The  spirit  may  be  methylated,  but  should  be  previously  dehydrated  to 
about  93  per  cent,  by  being  kept  in  contact  with  freshly-ignited  potassium 
carbonate.  A  Soxhlet's  tube  or  equivalent  arrangement  might  probably  be 
advantageously  employed  for  the  alcoholic  treatment  described  in  the  text. 


452  ASSAY   OF   CINCHONA  BARKS. 

small  to  affect  appreciably  the  accuracy  of  the  assumption  that 
the  alkaloids  are  weighed  in  the  anhydrous  state.  If  preferred, 
however,  the  temperature  may  be  raised  to  115°  C.^ 

For  the  assay  of  yellow  cinchona  bark,  ether  may  be  substituted 
for  the  chloroform  employed  in  the  above  process. 

c.  The  following  method  of  assay  is  due  to  P  r  o  1 1  i  u  s  {Arcliiv 
d.  Pharm.,  ccix.  85,  572),  with  precautions  suggested  by  D  e  Yr  ij, 
B  i  e  1,  and  others.  It  is  practically  the  process  of  the  German 
Pharmacopoeia  (1882): — Prepare  a  mixture  of  85  parts  of  ether 
(sp.  gr.  0-724  to  0*728),  10  parts  of  alcohol  (sp.  gr.  0-830  to 
0-834),  and  5  parts  of  ammonia  (sp.  gr.  0-960),  aU  hy  weighty 
making  100  parts  in  all.  Treat  10  or  20  grammes  (according  to 
its  supposed  richness)  of  the  previously  dried  and  very  finely- 
powdered  cinchona  bark  in  a  tared  glass-stoppered  bottle  with 
twenty  times  its  weight  of  the  above  solvent-mixture,  observe  the 
exact  weight  of  the  bottle  and  its  contents,  and  agitate  at  intervals 
during  four  hours.  If  any  loss  of  weight  occurs,  add  sufficient  of 
the  solvent-mixture  to  restore  it,  agitate  and  weigh  again.  Care- 
fully decant  into  a  flask  as  much  of  the  solution  as  can  be  poured 
off  perfectly  clear,  and  ascertain  the  quantity  taken  by  re-weighing 
the  stoppered  bottle.  Distil  off  the  ether,  evaporate  the  residual 
liquid  in  a  tared  beaker  at  100°,  and  weigh  the  residue  when 
thoroughly  dry.     Then  : — 

Weight  of  solvent-mixture  employed  x  weight  of  residue  _  T  total  crude  alkaloids 
Weight  of  alkaloidal  solution  decanted  ~  I       *"  bark  taken. 

The  crude  alkaloids  thus  obtained  are  dissolved  in  dilute 
hydrochloric  acid,  the  solution  filtered,  and  the  filtrate  made 
alkaline  with  caustic  soda  and  repeatedly  agitated  with  chloroform, 
which  is  separated,  evaporated,  and  the  residual  alkaloids  weighed 
after  drying  at  100°  in  the  usual  way.  De  Vrij  found  the 
purified  alkaloids  so  obtained  from  a  red  Java  bark  to  be  83-5  per 
cent,  of  the  total  crude  alkaloids  previously  extracted. 

^  With  a  few  modifications  of  minor  importance,  the  method  described  in 
the  text  is  that  used  by  most  quinologists.  One  well-known  authority  prefers 
to  work  on  a  very  large  quantity  of  the  bark  (about  2  lbs.).  Having  treated 
with  lime,  alcohol,  and  acid  in  the  manner  described  in  the  test,  he  pre- 
cipitates the  aqueous  solution  of  the  sulphates  with  soda,  filters,  washes 
slightly,  dissolves  the  precipitate  in  acetic  acid,  and  filters  from  any  undis- 
solved colouring-matter.  The  filtrate  is  divided  into  two  equal  parts,  A  and 
B.  A  is  precipitated  by  ammonia,  filtered,  and  the  filtrate  shaken  Avith 
chloroform,  which  is  then  used  to  dissolve  off  the  alkaloids  from  the  filter. 
The  solution  is  evaporated,  and  the  total  alkaloids  weighed,  after  drying  at 
115"  C.  B  is  treated  in  a  manner  similar  to  A,  but  the  chloroform  is  replaced 
by  ether.  The  alkaloid  thus  dissolved  is  called  "quinine,"  the  difference 
between  that  and  the  total  alkaloids  being  the  "other  alkaloids." 


PRECIPITATION   AS  PICRATES.  453 

d.  The  following  method  for  the  estimation  of  the  total  alkaloids 
of  cinchona  bark  is  that  of  H  a  g  e  r.  The  accuracy  of  the  method 
has  been  confirmed  by  0.  Me  din  {Zeit.  Anal.  Chem.,  viii.  477  ; 
ix.  447)  : — Ten  grammes  of  the  dried  and  finely-powdered  bark  are 
treated  for  a  short  time  with  100  c.c.  of  water  and  10  grammes  of 
caustic  potash  solution  of  1*35  specific  gravity.  The  mixture  is 
then  heated  and  kept  at  the  boiling-point  for  a  quarter  of  an  hour. 
Fifteen  grammes'  weight  of  diluted  sulphuric  acid  (sp.  gr.  1*11 5) 
is  next  added,  and  the  whole  boiled  for  twenty  minutes.  After 
cooling,  both  liquid  and  residue  are  transferred  to  a  measuring 
cylinder,  and  diluted  with  water  till  the  whole  has  a  volume  of 
110  c.c.^  The  liquid  is  then  passed  through  a  dry  filter,  and 
60  c.c.  of  the  filtrate  (=6  grammes  of  bark),  mixed  with  50  c.c. 
of  a  cold,  saturated,  aqueous  solution  of  picric  acid.  After 
standing  for  half  an  hour  the  precipitated  picrates  are  filtered 
off,  washed  with  a  little  cold  water,  dried  at  100°,  and  weighed. 
The  product  contains  42*5  per  cent,  of  its  weight  of  alkaloids, 
calculated  as  quinine.  A  preferable  plan  is  to  suspend  the 
washed  precipitate  in  cold  water,  add  excess  of  caustic  soda, 
and  agitate  with  chloroform.  The  chloroformic  solution  of  the 
alkaloids  is  then  treated  as  in  process  b.  The  picric  acid  method 
of  assaying  cinchona  barks  is  said  to  be  accurate,  easy,  and  ex- 
peditious. 

Separation  of  CincTiona  Bases. 

The  separation  of  the  alkaloids  of  cinchona  and  allied  barks  is 
an  extremely  complex  operation,  and  as  respects  the  rarer  alkaloids 
outside  the  scope  of  this  work.  But  the  accurate  separation  even 
of  the  commoner  alkaloids,  such  as  is  frequently  required  for  com- 
mercial purposes,  is  very  difficult,  and  its  accurate  performance 
presents  special  obstacles  to  an  inexperienced  analyst.  In  some 
cases  it  is  sufficient  to  determine  the  proportion  of  crystallisable 
quinine,  which  may  be  effected  as  described  below,  but  in  other  cases 
it  is  necessary  to  determine  also  the  cinchonine,  cinchonidine,  and 
occasionally  the  quinidine,  quinamine,  and  amorphous  alkaloids. 
For  the  separation  of  quinine  from  the  admixed  alkaloids,  ether  is 
usually  employed,  but  it  must  be  remembered  that  the  separation 
effected  by  this  solvent  is  not  an  absolute  one,  all  the  free  cinchona 
bases  being  more  or  less  soluble  in  ether,  especially  in  the  presence 
of  quinine.  The  anhydrous  sulphates  of  quinine  and  cinchonidine 
are  almost  insoluble  in  chloroform  free  from  alcohol  (see  page  430), 
but  in   presence  of  sulphate  of  cinchonine  or  quinidine  sensible 

^  This  is  allowing  100  c.c.  for  the  liquid,  and  10  c.c.  for  the  bulk  of  the 
residual  woody  fibre,  &c. 


454  SEPARATION    OF   CINCHONA   BASES. 

quantities  pass  into  solution.  Crystallisation  of  the  quinine 
sulphate  from  water  afi'ords  a  simple  and  fairly  accurate  mode  of 
separation,  which  has  the  advantage  of  being  similar  to  the  pro- 
cess employed  by  the  manufacturer,  and  hence  is  regarded  by  many 
as  furnishing  the  best  proof  of  the  yield  likely  to  be  obtained  in 
practice.  The  following  method  of  separating  the  quinine  in  the 
form  of  sulphate  is  described  by  J.  Muter  {Analyst^  v.  223) : — 
Treat  the  total  alkaloids,  or  the  ether-residue  from  20  grammes 
of  bark,  with  warm  distilled  water  slightly  acidulated  with  dilute 
sulphuric  acid,  till  the  mixture  is  perceptibly  acid.  Add  water  to 
make  70  c.c.  for  each  1  gramme  of  alkaloids  taken,  and  then  very 
dilute  soda  with  constant  stirring  till  the  liquid  is  exactly  neutral, 
with  a  faint  tendency  to  acidity.  Digest  the  liquid  at  85°  C.  for 
five  ininutes  ;  then  cool,  and  leave  at  15°  C.  for  one  hour.  Filter 
the  liquid  through  a  small  double  filter  (2|  inches  diameter),  the 
two  filters  being  previously  trimmed  to  equal  weight,  and  receive 
the  filtrate  in  a  graduated  cylinder.  Wash  carefully  with  water 
at  15°  C.  till  the  filtrate  and  washings  measure  90  c.c.  for  each 
1  gramme  of  the  mixed  alkaloids.  The  filter  and  contents  are 
now  completely  dried  at  100°  C,  and  weighed,  the  second  filter 
being  used  as  a  counterpoise.  To  the  weight  in  grammes  add 
•000817  gramme  for  each  c.c.  of  filtrate  and  washings.  The  sum 
divided  by  0*855  gives  the  corresponding  amount  of  crystallised 
sulphate,  and  this  number  multiplied  by  5  gives  the  crystallised 
quinine  sulphate  obtainable  from  100  grammes  of  dried  bark. 

The  quinine  sul])hate  so  obtained  is  apt  to  contain  cinchonidine 
sulphate,  and  should  be  tested  for  this  admixture  as  directed  on 
page  412.  The  remaining  alkaloids  may  be  recovered  from  the 
mother-liquors  by  concentrating  the  liquid  somewhat,  adding  soda 
in  excess,  and  agitating  with  chloroform.  On  evaporatmg  the 
chloroform,  the  bases  will  be  obtained  in  a  solid  state,  and  may  be 
separated  as  described  on  page  459. 

The  following  scheme  for  the  separation  of  the  principal 
cinchona  bases  is  founded  on  a  method  described  by  D  e  Vrij 
(Pharm.  Jour.,  [3],  ii.  642).  The  process  requires  a  considerable 
weight  of  alkaloids,  and  does  not  yield  strictly  accurate  results. 
Traces  of  quinidine  and  cinchonidine  are  dissolved  by  the  ether,  and 
are  only  recovered  on  treatment  of  the  amorphous  alkaloids  with 
a  limited  quantity  of  ether  as  directed.^  In  presence  of  much 
quinine  the  solubility  of  cinchonidine  in  ether  is  notably  increased. 

1  The  solubility  of  the  cinchona  bases  in  ether  at  15°  C.  is  given  by  A.  B. 
Prescott  as  being  :— for  quinine,  1  :  25  ;  quinidine,  1  :  30  ;  cinchonidine, 
1  :  188  ;  and  for  cinchonine,  1  :  371.  The  amorphous  cinchona  alkaloids  are 
readily  soluble  in  ether. 


DE    VRIJ'S   METHOD   OF   SEPARATION. 


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456  PRECIPITATION   AS   lODOSULPHATE. 

The  precipitation  of  the  quinine  as  herepathite  is  stated  by 
David  Howard  to  give  accurate  results  in  skilful  hands ;  but, 
instead  of  throwing  down  the  quinine  from  a  sulphuric  acid  solu- 
tion by  tincture  of  iodine,  De  Yrij  recommends,  in  his  more 
recent  papers,  the  use  as  a  precipitant  of  the  iodosulphate  of  the 
amorphous  cinchona  bases  commercially  known  as  "  quinoidine." 
This  forms  a  readily  soluble  iodosulphate,  and  by  employing  a 
previously  prepared  solution  of  it  any  error  from  the  formation  of 
periodised  iodosulphate    of    quinine  is  avoided.^     De  Vrij  directs 

^  Pharm.  Jour. ,  [3],  vi.  461 ;  xii.  601 .  One  part  of  commercial  ' '  quinoi- 
dine" is  heated  on  a  water-bath  with  2  parts  of  benzene,  whereby  the 
quinoidine  is  partly  dissolved.  The  cold,  clear  benzene-solution  is  shaken  with 
excess  of  dilute  sulphuric  acid,  an  aqueous  solution  of  the  acid  sulphate  of 
quinoidine  being  thus  obtained.  The  amount  of  alkaloid  is  then  determined 
in  a  small  portion  of  this  solution,  and  the  rest  is  slowly  treated  with  1  part 
of  iodine  and  2  of  potassium  iodide  dissolved  in  water  for  every  2  parts  of 
amorphous  alkaloid  known  to  be  present.  The  iodine  solution  must  be 
added  very  gradually,  with  vigorous  stirring,  so  that  no  part  of  the  quinoidine 
solution  shall  come  in  contact  with  excess  of  iodine.  A  fiocculent,  orange- 
coloured  precipitate  of  iodosulphate  of  quinoidine  is  formed,  which  by  slight 
elevation  of  temperature  coagulates  to  a  dark  brownish-red  resinoid  body. 
The  yellowish  liquid  is  poured  off,  and  the  precipitate  heated  to  100°  with 
water,  when  the  liquid  is  poured  away.  The  adhering  moisture  is  evaporated 
off  at  100°  C,  when  the  iodosulphate  remains  as  a  soft  and  tenacious  mass, 
which  becomes  brittle  on  cooling.  One  part  of  this  substance  is  dissolved  by 
heating  with  6  |)arts  of  alcohol  of  92  to  95  per  cent.  The  solution  is  allowed 
to  cool,  filtered,  evaporated  to  dryness,  and  the  residue  dissolved  in  5  parts  of 
cold  alcohol.     When  filtered,  the  solution  thus  obtained  is  ready  for  use. 

In  using  this  solution  for  the  determination  of  crystallisable  quinine  in  a 
mixture  of  cinchona  bases  (as  free  as  possible  from  cinchonidine),  1  part 
by  weight  of  the  alkaloid  is  dissolved  in  20  parts  of  alcohol  of  92  to  95 
per  cent.,  containing  1*5  per  cent,  of  sulphuric  acid  (H2SO4),  which  amount 
is  sufficient  to  convert  the  bases  into  acid  sulphates.  The  solution  is 
then  diluted  with  50  parts  of  unacidulated  alcohol.  To  this  liquid,  at  the 
ordinary  temperature,  the  iodosulphate  of  quinoidine  is  added  drop  by  drop 
from  a  burette,  with  constant  stirring,  as  long  as  a  dark  brownish-red  pre- 
cipitate of  herepathite  is  formed.  As  soon  as  all  the  quinine  has  been 
preci{)itated,  and  a  slight  excess  of  the  reagent  has  been  added,  the  liquor 
acquires  an  intense  yellow  colour.  The  beaker  is  now  covered  and  heated  on 
a  water-bath  till  the  liquid  begins  to  boil,  and  all  the  precipitate  is  dissolved, 
when  the  liquid  is  allowed  to  cool.  After  standing  twelve  hours,  the  beaker  is 
weighed  with  its  contents.  The  liquid  is  next  passed  through  a  small  filter, 
leaving  the  crystals  in  the  beaker,  which  is  then  again  weighed  to  ascertain 
the  weight  of  the  liquid.  The  crystals  on  the  filter  are  washed  back  into  the 
beaker,  and  as  much  alcohol  added  as  is  necessary  to  dissolve  the  crystals  at 
the  boiling-point.  When  quite  cold  the  beaker  is  again  weighed,  the  recrystal- 
lised  herepathite  collected   on   a   small   filter,  and  the  empty  beaker  again 


SEPARATION  OF   CINCHONA  BASES.  457 

the  addition  of  the  reagent  to  the  solution  of  the  mixed  alkaloids 
of  cinchona  bark,  but  it  has  been  pointed  out  by  Christensen, 
Shimoyama,  and  others  {Pharm.  Jour.,  [3],  xii.  441,  1016;  xvi. 
205 ;  xvii.  654),  that  cinchonidine,  if  present  in  notable  quantity, 
is  liable  to  be  precipitated  along  with  the  quinine,  and  hence  this 
base  should  be  separated  as  completely  as  possible  by  a  previous 
ether-treatment,  as  directed  on  page  455.  The  use  of  the  iodo- 
sulphate  of  quinoidine  prevents  any  subsequent  isolation  of  the 
amorphous  alkaloids  of  the  bark  under  examination. 

Instead  of  converting  the  quinine  in  the  ethereal  solution  B  into 
herapathite,  David  Howard  ( WaW  Diet.  Ghem.,  2nd  ed., 
ii.  177)  agitates  the  ethereal  liquid  with  excess  of  dilute  sulphuric 
acid,  and,  after  heating  to  boiling,  adds  dilute  ammonia  till  neutral 
to  litmus,  using  no  more  water  than  is  necessary.  On  cooling,  the 
quinine  crystallises  out  almost  entirely  as  sulphate,  which  salt  is 
almost  insoluble  in  a  cold  solution  containing  ammonium  sulphate. 
The  crystals  are  filtered  off,  washed  with  a  little  cold  water,  pressed 
between  blotting-paper,  and  dried  at  100°  C.  73*4  parts  of  the 
anhydrous  salt  represent  100  parts  of  the  crystallised  sulphate. 
The  product  should  be  tested  for  cinchonidine  (page  412),  which 
may  be  present  in  small  quantity.  The  alkaloids  existing  in  the 
mother-liquor  from  the  quinine  sulphate  are  then  recovered  by 
concentrating  the  liquid  somewhat,  adding  soda  in  excess,  and  shak- 
ing with  chloroform.  The  bases  are  extracted  from  the  separated 
chloroform  by  dilute  acetic  acid,  and  the  solution  treated  as  in  A. 

The  mixed  alkaloids  of  yellow  cinchona  bark  consist  chiefly 
of  quinine,  and  hence  the  portion  soluble  in  ether  represents  the 
most  useful  constituents  of  the  bark.  Pale  and  red  barks,  on  the 
other  hand,  contain  a  considerable  proportion  of  alkaloids  insoluble 

weighed.  The  difference  indicates  the  weight  of  the  mother-liquor,  which  is 
added  to  that  of  the  main  quantity. 

The  recrystallised  herepathite  obtained  as  above  is  washed  on  the  filter  with 
a  saturated  solution  of  herepathite  in  alcohol  of  92  per  cent.  The  adhering 
liquid  is  removed  as  far  as  possible  by  pressing  the  folded  filter  and  its  con- 
tents between  blotting-paper,  and  the  filter  is  then  air-dried.  The  precipitated 
herepathite  is  then  detached  from  the  filter,  dried  at  100°  till  constant,  and 
weighed.  The  amount  found  is  corrected  by  the  addition  of  that  remaining  in 
solution,  as  ascertained  by  calculation  from  the  weight  of  the  mot  her- liquor. 
One  hundred  grammes  of  alcohol  of  92  per  cent,  dissolve  "133  gramme  of  here- 
pathite at  24-5°  C,  and  '125  gramme  at  16°  C. 

The  weight  of  herepathite  found,  multiplied  by  '55055  gives  the  anhydrous, 
or  by  0*7409  the  corresponding  weight  of  crystallised,  sulphate  of  quinine. 
Instead  of  drying  the  recrystallised  herepathite,  it  might  probably  be  titrated 
with  standard  sodium  thiosulphate  solution.  21  "58  parts  of  iodine  thus  found 
represent  100  parts  of  herepathite. 


458  SEPARATION   OF   CINCHONA   BASES. 

or  sparingly  soluble  in  ether.  Hence  the  use  of  chloroform  in  the 
general  process  for  assaying  cinchona  barks  (see  page  451). 

In  some  cases,  the  alkaloids  soluble  in  ether  are  contaminated 
to  a  considerable  extent  with  colouring  matter.  In  this  event, 
the  following  is  a  good  method  of  obtaining  colourless  quinine 
sulphate : — The  ether-residue  is  dried  thoroughly  and  weighed. 
It  is  then  dissolved  in  30  c.c.  of  absolute  alcohol,  and  decinormal 
sulphuric  acid  cautiously  added  from  a  burette,  till  the  liquid  is 
neutral  or  very  faintly  acid  to  litmus-paper  or  methyl-orange. 
Each  c.c.  is  equivalent  to  0*324  gramme  of  anhydrous  alkaloids. 
The  liquid  is  next  evaporated  nearly  to  dryness,  and  a  measure  of 
decinormal  sulphuric  acid  added  equal  to  that  previously  required 
for  neutralisation.  Thirty  c.c.  of  hot  water  are  added,  and  the 
liquid  boiled  till  complete  solution  results.  Purified  animal 
charcoal  is  next  added,  in  quantity  equal  to  the  weight  of  the 
ether-residue,  the  liquid  heated  on  the  water-bath  for  twenty 
minutes,  filtered,  and  the  residue  washed  twice  with  boiling  water 
acidulated  with  sulphuric  acid.  The  filtrate  is  brought  to  a  con- 
centration of  70  c.c.  for  each  1  gramme  of  ether-residue  taken, 
and  then  cautiously  neutralised  with  caustic  soda,  and  further 
treated  as  described  on  page  451. 

Instead  of  commencing  the  separation  of  the  alkaloids  by  ether, 
Mo  ens  recommends  that  the  neutral  solution  of  the  mixed 
alkaloids  should  be  treated  with  excess  of  solution  of  potassium 
sodium  tartrate  (RocheUe  salt),  which  throws  down  the  quinine 
and  cinchonidine  as  tartrates.  The  same  procedure  is  adopted  in  the 
British  Pharmacopoeia  (see  page  450).  The  precipitated  tartrates 
are  washed  with  a  little  cold  water,  decomposed  by  excess  of  alkali, 
and  the  quinine  and  cinchonidine  separated  by  ether ;  the  quinine 
dissolved  being  either  directly  weighed,  or,  preferably,  converted 
into  sulphate  and  tested  for  cinchonidine  (page  412). 

The  estimation  of  the  relative  proportions  of  quinine  and  cin- 
chonidine in  the  mixed  tartrates,  by  observing  the  optical  activity 
(page  415),  has  been  recommended  by  several  chemists,  but  in 
practice  it  is  difficult  to  obtain  the  alkaloids  in  a  sufficiently  pure 
condition  to  render  the  results  trustworthy. 

The  following  method  for  the  separation  of  the  cinchona  bases 
insoluble,  or  nearly  insoluble,  in  ether  may  be  applied  to  the 
residue  left  on  treatment  of  the  mixed  alkaloids  with  ether,  as  in 
De  Vrij's  process  (page  454).  It  may  also  be  applied  directly 
to  the  mixed  alkaloids  extracted  from  a  sample  of  bark,  in  which 
case  it  may  be  carried  on  simultaneously  with  Muter's  process  for 
the  production  of  crystallised  quinine  sulphate  as  described  on 
page  454. 


SEPARATION   OF   CINCHONA   BASES. 


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460  TITRATION   OF  PRECIPITATES. 

The  foregoing  process,  with  experience,  gives  very  good  results, 
the  sum  of  the  separated  alkaloids  frequently  amounting  to  99  per 
•cent,  of  the  mixed  bases  operated  on.  It  is  well  suited  for  the 
assay  of  Indian  barks.  The  least  satisfactory  part  of  the  process 
is  the  separation  of  the  cinchonine  from  the  amorphous  bases  by 
dilute  spirit.  A  cautious  employment  of  ether  would  perhaps  be 
preferable.  If  the  process  of  separation  be  conducted  simul- 
taneously with  the  determination  of  the  crystallised  quinine 
sulphate  in  another  portion  (page  454),  the  whole  analysis  can 
be  completed  in  about  six  hours. 

According  to  Hielbig  (Pharm.  Zeitsch.  f.  Russland,  1888; 
Analyst,  xiii.  207)  the  presence  of  much  quinidine  prevents  the 
complete  precipitation  of  the  cinchonidine  and  quinine  as  tartrates  ; 
while  the  precipitate  with  potassium  iodide,  if  tenacious  or  resinous 
instead  of  crystalline,  contains  cinchonine,  with  or  without  quini- 
dine. (It  seems  more  probable  that  the  resinous  precipitate  con- 
sists of  the  hydriodides  of  amorphous  alkaloids,  which  can  be  kept 
in  solution  by  moderate  addition  of  alcohol.) 

The  directions  in  the  foregoing  table  can  be  modified  with  con- 
siderable saving  of  time  by  titrating  the  alkaloids  and  their  salts 
instead  of  weighing  them.  Thus,  for  the  determination  of  the 
cinchonidine,  the  washing  of  the  precipitated  tartrate  with  cold 
water  should  be  omitted,  and  the  filter  containing  the  precipitate 
and  the  adhering  Eochelle  salt  solution  immersed  in  boiling  water. 
A  drop  of  phenolphthalein  solution  is  then  added,  and  the  liquid 
titrated  with  -^  caustic  alkali.  As  Eochelle  salt  is  perfectly 
neutral  to  phenolphthalein,  and  as  tartrate  of  cinchonidine  (and  of 
quinine)  acts  just  like  an  equivalent  amount  of  free  tartaric  acid, 
the  weight  of  cinchonidine  can  be  readily  calculated  from  the 
measure  of  standard  alkali  used.  Each  1  c.c.  of  -^  NaHO  neu- 
tralised represents  0*0147  gramme  of  cinchonidine  (or  other  alka- 
loid) precipitated  as  tartrate  (A.  H.  Allen). 

An  exactly  similar  method  is  applicable  to  the  treatment  of  the 
precipitate  produced  by  potassium  iodide.  This  should  be  washed 
with  a  little  of  the  precipitant  instead  of  with  water,  and  then 
immersed  together  with  the  filter  in  boiling  water.  On  titrating 
with  -^-^  alkali  and  phenolphthalein  each  1  c.c.  of  the  standard 
solution  required  represents  0'0162  gramme  of  quinidine  pre- 
cipitated as  hydriodide.^ 

The  chloroformic  solution  of  the  cinchonins  may  be  directly 
titrated  with  standard  acid  and  methyl-orange  (see  p.  131)  instead 
of  being  evaporated  to  dryness  ;  but,  of  course,  the  amount  found  will 
include  any  amorphous  alkaloid  also  extracted  by  the  chloroform. 

^  This  procedure  does  not  dispense  with  the  necessity  of  making  a  correction 
for  the  amount  of  quinidine  lost  in  the  mother-liquor  and  washings. 


BERBERIS  ALKALOIDS. 


461 


BERBERINE  AND  ITS  ASSOCIATES. 

Berberine  is  an  alkaloid  occurring  in  a  very  large  number 
of  plants,  in  many  cases  in  association  with  one  or  more  of  the 
alkaloids,  berbamine,  oxyacanthine,  hydrastine,  canadine,  &c.  It 
is  the  only  natural  basic  colouring  matter  receiving  practical 
application  as  a  dye. 

The  i)rincipal  sources  of  berberine  and  the  associated  alkaloids 
are  the  roots  of  the  following  plants  : — 


Plant. 

Alkaloids,  &c. 

Berberis  vulgaris  (Barberry),i 

Berberis  aquifolium, 

Coptis  trifolia, 

Coptis  teeta  (India),   .... 

Hydrastis  Canadensis    (Golden 
seal), 

Jateorhiza  Calumba  or  Cocculus 
palmatus  (Calumba  root), 

Menispermum  Canadense, 

Berberine  ;  oxyacanthine  ;  berbamine  ;  and  at 
least  two  other  alkaloids  (Hess  e). 

Berberine,  2 '35  per  cent.;    oxyacanthine,  2-82 
per  cent. 

Berberine,  4  per  cent. 

Berberine,  8^  per  cent.;   coptinine  (crystallis- 
able ;  Gross). 

Berberine,  ]-3  to  1-8  per  cent.;  hydrastine,  1*5 
per   cent. ;    canadine  ;    xanthopuccine  ;    &c. 
Also  meconin  and  phytostearin. 

Berberine ;   columbic   acid ;    and  the  neutral 
principle  columbin. 

Berberine ;  oxyacanthine ;  menispermine  ;  men- 
ispine. 

Berberine  has  also  been  found  in  Woodumpar,  a  yellow 
dye-wood  from  Upper  Assam;  in  S  t  John's  wood,  from  Rio 
Grande;  in  Berberis  aristat a,  Caulophyllum  thalictro'ides,  Coscinium 
fenestratum  (Ceylon  Calumba  wood),  Coelocline  ;polycarpa,  Podo- 
'phyllum  pellatwn,  Xanthorhiza  ayiifolia,  and  Xanthoxylum  clava- 
Hercules.     Hydrastine  occurs  also  in  Stylopliorum  diphyllum. 

Berberine.    C20H17NO4 ;  or  Ci8Hii(O.CH3),N02. 

Berberine  is  isolated  from  the  root  of  Hydrastis  Canadensis  by 
boiling  with  water,  evaporating  the  decoction  to  an  extract,  and 
exhausting  with  strong  alcohol.  One-fourth  o£  its  volume  of  water 
is  added  to  the  filtered  alcoholic  solution,  the  alcohol  distilled  off, 
and  the  residue  treated  with  dilute  sulphuric  acid.  Berberine 
sulphate  crystallises    out,    and   is    decomposed   by  freshly-precipi- 

^  A  concentrated  liquid  extract  of  barberry  root  still  receives  a  limited 
application  for  dyeing  silk  and  leather  yellow.  In  America,  the  root-bark  is 
commonly  used,  but  in  Europe  the  entire  root  is  generally  employed. 


462  CHARACTERS   OF   BERBERINE. 

tated  hydroxide  of  lead.  The  alkaloid  may  also  be  converted 
into  the  sparingly  soluble  nitrate  or  hydrochloride  instead  of  the 
sulphate. 

I^.  Wolff  recommends  a  previous  treatment  of  the  root  with 
petroleum  ether  to  remove  fixed  oil. 

Berberine  may  be  isolated  from  barberry  or  calumba  root  by 
exhausting  the  material  with  alcohol,  evaporating  off  the  spirit, 
taking  up  the  residue  with  water,  and  treating  the  filtered  solution 
with  excess  of  hydrochloric  acid,  when  berberine  hydrochloride 
crystallises  out.  The  salt  may  be  purified  by  re-solution  in  alcohol 
and  precipitation  by  ether> 

Berberine  crystallises  with  difficulty  in  small,  concentrically 
grouped  prisms,  or  bright  yellow,  silky  needles.^  When  air-dried, 
the  crystals  appear  to  contain  5  J  aqua  (W.  H.  Per  kin,  jun.), 
of  which  3  aqua  is  driven  off  at  100".  At  this  temperature  the 
crystals  lose  their  lustre  and  become  yellowish-brown,  at  110°  the 
change  is  very  rapid,  and  above  160°  total  decomposition  occurs. 
Fleitmann  gives  120°  as  the  melting-point  of  berberine,  but 
P  e  r  k  i  n  considers  this  figure  too  low.^ 

When  warmed,  berberine  emits  a  faint  but  peculiar  odour 
resembling  quinone. 

Berberine  has  a  persistent,  very  bitter  taste,  and  is  employed 
medicinally  in  doses  of  2  to  5  grains.  Sixty  grains  have  been 
taken  by  man  without  injury,  but  the  alkaloid  is  poisonous  to  dogs 
and  other  of  the  lower  animals. 

Berberine  dissolves  in  500  parts  of  cold  water,  and  more  readiiy 
on  boiling.  The  solution  is  neutral  to  litmus.  It  is  sparingly 
soluble  in  cold,  but  readily  in  hot  alcohol,  and  in  amylic  alcohol. 
Berberine  is  slightly  soluble  in  chloroform  and  benzene,  and  in- 
soluble in  ether  (separation  from  oxyacanthine  and  hydrastine) 
and  petroleum  spirit.     It  is  said  to  be  taken  up  with  difficulty 

^  Berberine  may  also  be  prepared  by  precipitating  an  aqueous  decoction  of 
barberry  root  with  lead  acetate,  and  treating  the  concentrated  filtrate  with 
excess  of  sulphuric  acid.  The  precipitate  of  berberine  sulphate  is  washed  with 
cold  water,  and  separated  from  lead  sulphate  by  solution  in  boiling  water, 
which  on  cooling  deposits  the  salt  in  yellow  needles. 

2  An  orange  colour,  or  other  shade  darker  than  bright  yellow,  is  indicative 
of  impurity. 

^E.  Schmidt  has  obtained  some  evidence  that  berberine  pre pai'ed  from 
the  commercial  sulphate  is  occasionally  a  mixture  of  berberine  with  methy  1  - 
berberine.  He  obtained  pure  berberine  by  converting  the  alkaloid  into 
the  acetone  compound,  B,C3H60,  from  whit;h  the  free  base  was  liberated  by 
heating  in  alcoholic  solution.  Thus  obtained,  berberine  contained  6  aqua, 
all  of  which  was  lost  at  100°  C.  The  anhydrous  alkaloid  scarcely  began  to 
darken  below  150°. 


REACTIONS  OF   BERBERINE.  463 

from  its  acidulated  solutions  by  amylic  alcohol,  chloroform,  and 
benzene.^ 

When  treated  with  a  fixed  caustic  alkali,  berberine  is  coloured 
brown,  and  on  boiling  a  resinous  mass  separates.  On  distilling 
berberine  with  milk  of  lime,  quinoline  is  formed.  Fusion 
with  caustic  potash  produces  berberic  acid,  CgHgO^,  and  an 
acid  of  the  composition  CgHgOg. 

When  boiled  with  excess  of  fuming  hydriodic  acid,  two 
methyl  groups  are  eliminated  and  a  salt  of  berberoline, 
CigH^i(OH)2N02,  formed.  On  rendering  the  diluted  liquid 
slightly  alkaline  by  ammonia,  an  intense  blackish-blue  coloration 
is  obtained,  probably  owing  to  oxidation.  Nitric  acid  gives,  with 
berberoline,  a  magnificent  violet  coloration,  which  on  standing  or 
warming  changes  to  a  deep  reddish-brown. 

Concentrated  nitric  acid  dissolves  berberine  to  a  dark,  reddish- 
brown  liquid,  which  on  dilution  with  water  gives  a  yellow  flocculent 
precipitate  partly  soluble  in  ammonia.  If  the  dark  solution  of 
berberine  in  strong  nitric  acid  be  warmed  oxidation  rapidly  occurs, 
with  formation  of  berberonic  acid  (a  pyridine-tricarboxylic 
acid,  page  112),  oxalic  acid,  and  other  products. 

Potassium  permanganate  in  presence  of  potassium  carbonate 
oxidises  berberine  with  formation  of  hemipinic  acid, 
Ci^HjoOg,  and  other  products  ( W.  H.  P  e  r  k  i  n,  jun.,  Jour.  Chem. 
Soc,  Iv.  71). 

By  the  action  of  nascent  hydrogen,  berberine  is  reduced  to 
hydroberberine,  CgoHg^NO^. 

Berberine  dissolves  in  concentrated  sulphuric  acid  with  orange- 
yellow  colour,  changing  to  olive-green  on  warming.  On  adding 
potassium  bichromate,  or  other  oxidising  agent,  a  black  colour 
changing  to  violet  (or  brown-violet  changing  to  brownish-yellow)  is 
obtained.  Frohde's  reagent  gives  a  brown  or  green  colour  with 
berberine ;  or,  according  to  Hirschhausen,  an  immediate 
yellow,  changing  through  dark  brown  to  violet-brown.  Sulpho- 
vanadic  acid  is  stated  to  give  a  fine  violet  coloration. 

^  According  to  E.  Schmidt  {Pharm.  Zeit.,  18H7,  page  542),  berberine  has 
a  remarkable  tendency  to  combine  with  neutral  solvents,  such  as  alcohol,  ether, 
acetone,  and  chloroform,  to  form  crystalline  compounds.  When  berberine 
and  chloroform  are  mixed  in  molecular  proportions,  they  unite  to  form  a 
beautiful  crystalline  body,  permanent  at  100°.  This  does  not  appear  to  be  a 
mere  addition-product,  since  it  is  not  decomposed  by  acids  simply  into  ber- 
berine and  chloroform,  but  yields  decomposition-products  of  the  latter.  Ber- 
berine can  also  combine  with  a  second  molecule  of  chloroform,  but  this  behaves 
like  water  of  crystallisation.  Schmidt  has  also  described  a  compound  of 
berberine  with  acetone,  of  the  formula  C^ 


464  SALTS   OF   BERBERINE. 

Berberine  is  also  characterised  by  the  insolubility  of  many  of  its 
salts  {e.g.,  the  chromate,  picrate,  hydriodide,  chloroplatinate,  auro- 
chloride),  and  the  sparing  solubility  of  others  in  presence  of  excess 
of  mineral  acid. 

On  pouring  chlorine-water  (avoiding  excess)  on  to  a  solution  of 
berberine  strongly  acidulated  with  hydrochloric  or  sulphuric  acid, 
a  zone  of  bright  red  colour  is  formed  at  the  junction  of  the  liquids, 
and  is  still  recognisable  as  a  pink  coloration  in  a  dilution  of 
250,000.1 

On  cautiously  adding  iodised  potassium  iodide  (avoiding  excess) 
to  a  solution  of  a  berberine  salt,  BHI3  is  thrown  down  as  an  ex- 
tremely insoluble  red-brown  precipitate,  which  crystaUises  from 
strong  alcohol  in  red  needles,  or  on  adding  water  in  green  iridescent 
scales  which  completely  polarise  light. 

Mayer's  reagent  yields  with  berberine  solutions  a  precipitate  of 
the  approximate  composition  BgHgHgl^,  containing,  after  drying  at 
100°,  from  50  to  52  per  cent,  of  the  alkaloid. 

Salts  op  Berberine. 

Berberine  is  a  weak  base,  but  forms  definite  and  readily  crystal- 
lisable  salts  with  acids.  The  salts  have  a  bitter  taste,  and  are 
mostly  very  sparingly  soluble,  the  pyrophosphate  and  acetate 
being  exceptions. 

Berberine  Nitrate,  B,HN03,  separates  in  fine  yellow  needles  on 
acidulating  a  warm  aqueous  or  alcoholic  solution  of  berberine  with 
nitric  acid.  It  is  soluble  in  about  500  parts  of  cold  water,  more 
readily  in  hot,  and  almost  insoluble  in  alcohol  or  water  strongly 
acidulated  with  nitric  acid.  It  does  not  darken  or  undergo  other 
change  at  100°  C. 

Berberine  Hydrochloride,  B,HCl+2  aq,  is  precipitated  in  golden 
yellow  needles  on  adding  hydrochloric  acid  to  a  warm  aqueous 
solution  of  the  alkaloid.  It  requires  about  500  parts  of  cold  water 
for  solution,  and  is  almost  insoluble  in  alcohol  or  dilute  hydro- 
chloric acid.  The  salt  is  with  difficulty  decomposed  by  bases,  the 
liberated  alkaloid  being  apt  to  retain  chlorine.  Prolonged  diges- 
tion with  litharge  fails  to  decompose  it  completely,  but  silver  oxide 
readily  decomposes  the  solution.  Berberine  hydrochloride  darkens 
to  an  orange  colour  when  heated  to  about  60°  C,  but  regains  its 
original  colour  on  cooling.  By  prolonged  exposure  at  100°  the 
colour  changes  permanently,  and  much  of  the  salt  becomes  readily 
soluble  in  cold  water,  with  red  colour. 

BHAuCl^  is  amorphous,  brown,  and  quite  insoluble  in  water. 

^  Bmcine  gives  a  similar  reaction  with  chlorine-water,  but  the  original 
solution  is  colourless,  and  the  reaction  produced  less  permanent  than  with 
berberine. 


OXYACANTHINE.  46§ 

It  crystallises  from  boiling  dilute  alcohol  in  chestnut  brown 
needles,  unchanged  at  100°.  BgHgPtClg  forms  a  yellowish  pre- 
cipitate, almost  insoluble  in  all  the  ordinary  solvents.  It  may 
be  crystallised  from  boiling  amylic  alcohol,  in  which  it  is  slightly 
soluble. 

Berherine  Hydriodide,  B,HI,  obtained  by  precipitation,  forms 
minute  yellow  needles,  extremely  insoluble  in  cold  water  or  potas- 
sium iodide  solution.  It  does  not  darken  or  suffer  other  change 
at  100°.  BHIg  is  precipitated  on  cautiously  adding  iodised 
potassium  iodide  (carefully  avoiding  excess)  to  a  solution  of  a 
berberine  salt  in  hot  spirit.  It  is  quite  insoluble  in  cold  water. 
When  recrystallised  from  hot  alcohol,  the  smaller  crystals  trans- 
mit light  which  is  completely  polarised  (compare  Herepathite, 
page  403). 

Berberine  Sulpliate,  ^,11^0^^  is  met  with  in  commerce  both  in  the 
amorphous  state  and  crystallised.  The  latter  form,  which  is  consider- 
ably the  higher  piiced,  can  be  prepared  by  dissolving  15  grammes 
of  the  amorphous  preparation  in  a  boiling  mixture  of  250  c.c.  of 
alcohol  with  8  of  acetic  acid,  when  on  cooling  the  crystallised  salt 
separates  out.  It  has  an  orange  colour,  and  is  permanent  in  the 
air  when  free  from  impurity.  It  is  soluble  in  about  100  parts 
of  water.  According  to  J.  U.  Lloyd  {Ar)ier.  Drug.,  Sept.  1884), 
the  yellow  crystalline  powder  obtained  by  heating  commercial  ber- 
berine sulphate  with  ammonia  and  shaking  with  ether  is  not  the 
free  alkaloid,  as  commonly  assumed,  but  a  neutral  sulphate,  B2H2SO4, 
^hicli  is  readily  soluble  in  water. 

BjHgCrO^  is  obtained  in  orange-yellow  needles  on  adding  potas- 
sium bichromate  to  a  boiling  and  very  dilute  solution  of  a  salt  of 
berberine.  The  salt  separates  entirely  on  cooling,  and  is  extremely 
insoluble  in  cold  water  or  an  excess  of  the  precipitant. 

Berberine  Picrate  requires  45,000  parts  of  cold  water  for  solu- 
tion. As  a  consequence,  on  mixing  aqueous  solutions  of  berberine 
and  picric  acid  in  equivalent  proportions  and  filtering,  a  liquid  is 
obtained  free  from  yellow  colour  or  bitter  taste. 

Berberine  Acetate  is  prepared  by  adding  berberine  sulphate  to 
a  solution  of  a  potassium  acetate  in  rectified  spirit,  and  heating 
gently  till  the  yellow  salt  has  dissolved.  After  cooling,  the  liquid 
is  filtered  from  the  potassium  sulphate,  evaporated  to  a  syrup,  and 
shaken  with  ether,  when  berberine  acetate,  B(C2H402)9,  is  pre- 
cipitated as  a  crystalline  orange  powder.  It  is  readily  soluble  in 
water  and  alcohol,  nearly  insoluble  in  ether,  and  loses  acid  on 
exposure  to  air. 

OxYACANTHiNE,  CigHigNOg.  This  base  is  contained  in  Berberis 
vulgaris,  and  remains  in  the  mother-liquor,  from  which  the  berberine 

VOL.  III.  PART  II.  2  G 


466  OXYACANTHINE.     BERB  AMINE. 

has  been  separated  as  hydrochloride.  The  liquid  is  treated  with 
caustic  soda,  when  a  dark-coloured  precipitate  is  thrown  down,  from 
which  ether  dissolves  oxyacanthine,  berbamine,  and  an  unnamed 
alkaloid,  while  another  brown-coloured  amorphous  base  remains 
undissolved.  The  ethereal  solution  is  treated  with  acetic  acid,  and 
the  resultant  acetate  decomposed  by  sodium  sulphate,  when  oxy- 
acanthine sulphate  is  precipitated,  berbamine  remaining  in  solution. 
On  decomposing  the  solution  of  oxyacanthine  sulphate  with 
ammonia  the  free  alkaloid  is  precipitated  in  flocks,  which,  after 
drying  at  100°,  melt  at  138°-150°;  but  when  crystallised  from 
alcohol  or  ether  it  forms  anhydrous  needles  which  melt  at  208°— 
214°.  Oxyacanthine  is  readily  soluble  in  chloroform  and  benzene, 
but  only  sparingly  in  petroleum  spirit.  It  may  be  separated  from 
berberine  by  extracting  the  ammoniacal  solution  with  ether  or 
chloroform.  From  its  acidulated  solutions  it  is  not  extracted  by 
petroleum  spirit  or  benzene,  and  only  sparingly  by  chloroform. 
Oxyacanthine  is  dextro-rotatory  in  chloroformic  solution  (for  4  per 
cent,  at  15°,  S,= -f  131-6°).  BHCI-J-2H2O  forms  small  colour- 
less needles,  the  2  per  cent,  aqueous  solution  of  which  shows 
Sd=  -1-163"6°.  Hot  strong  solutions  are  coloured  green  by  ferric 
chloride.  Oxyacanthine  closely  resembles  narcotine.  Like  mor- 
phine, it  reduces  iodic  acid.  Concentrated  sulphuric  acid,  with 
or  without  molybdic  acid,  is  stated  to  give  no  colour  at  first,  but 
on  standing  or  heating  a  yellow  colour  is  developed ;  according  to 
L.  V.  Hirschhausen  {Zeit  Anal.  CfJiem.,  xxiv.  163),  Frohde's 
reagent  gives  an  immediate  violet  coloration,  changing  to  yellowish 
green  at  the  edges. 

When  heated  with  caustic  potash  and  a  little  water,  oxyacan- 
thine melts  to  a  brown  mass  which  floats  on  the  fused  alkali. 
This  consists  of  the  potassium  derivative  of  /3-o  x  y  a  c  a  n  t  h  i  n  e, 
a  body  probably  difiering  from  the  parent  alkaloid  by  the 
elements  of  water.  A  similar  change  occurs  very  readily  even 
at  the  ordinary  temperature,  by  the  action  of  alcoholic  potash 
or  baryta  on  a-oxyacanthine.  Ether  fails  to  extract  the  ^-modi- 
fication from  the  alkaline  solution.  Hydrochloric  acid  preci- 
pitates /5-oxyacan thine,  which  is  soluble  both  in  alkalies  and 
excess  of  acid.  With  much  acid,  a-oxyacanthine  hydrochloride  is 
precipitated. 

Berbamine,   CigHij^NOg,    the  second  Berheris   alkaloid  soluble 
in  ether,  was  obtained  by  Hesse  {BeiHchte,  xix.  3190)  by  adding 
sodium  nitrate  to  the  liquid  from  which  oxyacanthine  had  beea^b*., 
thrown   down   as   sulphate.      The  precipitated  berbamine   nitrate   "^ 
when  decomposed  by  ammonia  yields  a  crystalline  precipitate  of 
the  free  base,  which  crystallises  from  alcohol  in  small  plates  con- 


HYDRASTINE.  467 

taining  2  aq.  and  melting  at  156°.  The  salts  are  crystallisable  and 
readily  soluble.  B2H2PtCIg  is  yellow,  crystalline,  and  only  slightly 
soluble  in  water. 

Hydrastine.  C^jB-^^I^Oq;  or  Ci9Hi5(O.CH3)2N02  (see  also 
page  470). 

This  interesting  base  occurs  with  berberine  (and  canadine)  in  the 
root  of  Ihjdrastis  Canadensis  or  Golden  S  e  a  1.^  Perrins  found 
1 J  per  cent,  in  the  dried  root,  but  the  yield  in  manufacture  is  from 
J  to  f  per  cent.  It  also  occurs  in  Shjlophorum  diphyllum.  Hy- 
drastine differs  from  berberine  in  being  colourless,  but  commercial 
medicinal  preparations  of  berberine  from  Hydrastis  are  not  un- 
frequently  called  hydrastine.^ 

Hydrastine  forms  colourless  or  milk-white  four-sided  prisms, 
melting  at  132°  and  decomposing  at  a  higher  temperature  with  an 
odour  of  phenol. 

Free  hydrastine  is  tasteless  and  odourless,  but  the  salts  have  an 
acrid  taste.  The  alkaloid  is  the  chief  if  not  the  only  active 
principle  of  Hydrastis  Caicadensis.^  It  is  poisonous  in  large  doses, 
3  grains  being  fatal  to  a  frog  in  four  minutes.  It  resembles 
strychnine  in  causing  death  by  arresting  the  respiratory  move- 
ments in  a  tonic  spasm. 

Hydrastine  is  insoluble  in  water,  and  nearly  insoluble  in  alk9,line 
solutions.      It  dissolves  in  120  parts  of  alcohol,  in  1 J  parts  of  chloro- 

^F.  Wilhelm  extracts  the  coarsely-powdered  root  of  Hydrastis  Canadensis 
with  boiUng  water  acidulated  with  acetic  acid,  evaporates  the  decoction  to  a 
syrup,  and  adds  excess  of  dilute  sulphuric  acid.  After  standing,  the  berberine 
sulphate  which  crystallises  out  is  filtered  off,  and  the  filtrate  neutralised  with 
ammonia.  The  precipitate  contains  much  hydrastine,  and  on  again  filtering 
and  adding  excess  of  ammonia  to  the  filtrate  a  further  precipitate  is  produced, 
which  is  said  to  contain  canadine.  Both  precipitates  when  boiled  with  ethyl 
acetate  give  solutions  which  on  cooling  deposit  hydrastine  in  large  crystals, 
which  may  be  purified  by  crystallisation.  The  crystals  from  the  second 
ammonia  jirecipitate  are  much  purer  than  those  from  the  first.  By  slow 
evaporation  of  the  ethyl  acetate  solution  the  hydrastine  is  obtained  in  prisms 
as  large  as  walnuts. 

Eberhardt  purifies  hydrastine  by  dissolving  tiie  freshly-precipitated 
alkaloid  in  a  minimum  of  boiling  chloroform,  filtering  through  glass-wool,  and 
pouring  the  solution  into  excess  of  cold  alcohol.  On  shaking  the  liquid 
vigorously  for  some  minutes,  the  hydrastine  separates  as  a  fine  crystalline 
precipitate,  which  is  subjected  to  a  repetition  of  the  process  and  recrystallised 
from  boiling  alcohol. 

•^  The  root  of  Golden  Seal  is  a  bitter  tonic  analogous  to  calumba.  It  is 
exhibited  in  the  form  of  powder  and  in  doses  of  8  to  24  grains.  The  hydro- 
chlorides of  the  mixed  alkaloids  of  golden  seal  are  sometimes  sold  under  the 
name  of  "hydrastine." 


468  SALTS  OF  HYDRASTINE. 

form,  in  16  of  benzene,  and  in  83  of  ether.  It  is  quite  insoluble  in 
petroleum  spirit.  The  solubility  of  hydrastine  in  ether  may  be 
utilised  to  separate  it  from  berberine.  Hydrastine  is  Isevo-rotatory, 
Soin  chloroformic  solution(  1-2759  gramme  in  50c.c.)  being—  67-8°.^ 

Hydrastine  is  a  feeble  base,  and  is  completely  extracted  by 
chloroform  from  solutions  freely  acidulated  with  hydrochloric  acid. 
In  part,  however,  it  is  dissolved  as  hydrochloride,  which  salt  is 
very  soluble  in  chloroform. 

With  the  exception  of  the  picrate,  the  salts  of  hydrastine  are 
generally  uncrystallisable,  or  are  obtainable  in  crystals  by  special 
means  only.  Most  of  them,  except  the  tannate  and  picrate,  are 
soluble  in  water,  the  solutions  having  an  acid  reaction. 

Hydrastine  hydrochloride  and  sulphate  are  used  in  medicine.^ 
B,HC1  is  best  prepared  by  passing  dry  hydrochloric  acid  gas  over 
the  surface  of  a  solution  of  hydrastine  in  anhydrous  and  alcohol- 
free  ether.  After  drying  over  sulphuric  acid  the  precipitate  forms 
a  micro-crystalline  powder  easily  soluble  in  water  and  chloroform. 
B,H2S04  is  similarly  obtained  by  cautiously  adding  a  solution  of 
strong  sulphuric  acid  in  ether  to  an  ethereal  solution  of  hydrastine. 
The  salt  readily  takes  up  water  and  forms  a  gummy  mass. 

Hydrastine  solutions  give  no  colour-reaction  with  chlorine-water. 
With  iodised  potassium  iodide  they  yield  a  deep  brown  flocculent 
precipitate. 

Hydrastine  may  be  approximately  determined  by  titration  with 
Mayer's  reagent- (page  141),  but  the  precipitating  power  of  the 
solution  is  materially  affected  by  the  dilution  of  the  liquid. 

Picric  acid  forms  in  hydrastine  solutions  a  yellow  amorphous 
precipitate  of  the  picrate,  BA-t-4  aq,  which  is  deposited  in 
splendid  yellow  needles  from  its  solution  in  boiling  alcohol. 

Solutions  of  hydrastine  are  precipitated  by  potassium  bichromate. 
On  touching  the  separated  precipitate  with  a  drop  of  strong  sul- 
phuric acid,  it  instantly  becomes  bright  red,  the  colour  fading  in  a 
few  seconds.  This  behaviour  distinguishes  hydrastine  from  strych- 
nine and  gelsemine  (page  368). 

If  a  solution  of  hydrastine  be  acidulated  with  sulphuric  acid, 
and  a  few  drops  of  a  decinormal  solution  of  potassium  permanganate 
added,  the  colour  of  the  reagent  is  instantly  discharged,  and  an 
intense  blue  fluorescence  is  developed.     A  single  drop  of  a  1  per 

1  The  figure  for  specific  rotation  given  in  the  text  is  that  of  F  r  e  u  n  d  and 
Will.  Eijkinan  practically  confirms  this.  F.  B.  P  o  w  e  r  ( Pharm.  Jour.,  [3], 
XV.  298)  gives  the  widely  different  figure  —170°. 

2  The  crystallised  sulphate  of  hydrastine  advertised  by  some  manufacturers 
is  simply  sulphate  of  berberine,  to  which  the  name  hydrastine  is  persistently 
misapplied. 


REACTIONS  OF   HYDRASTINE.  469 

cent,  solution  of  hydrastine  when  treated  in  this  way  renders  a 
large  test-tube  of  liquid  strongly  fluorescent  (A.  B.  Lyon  s, 
PJiarm.  Jour.,  [3],  xvi.  880).  Excess  of  permanganate  must  be 
avoided,  or  both  the  alkaloid  and  fluorescent  product  will  be 
destroyed.  The  fluorescent  body  differs  from  sesculin  in  not  being 
extracted  from  either  acid  or  alkaline  solutions  by  chloroform  or 
etlier,  and  in  not  having  the  fluorescence  intensified  by  addition  of 
alkali.i 

The  colour-reactions  of  solid  hydrastine  have  been  re-investigated 
by  A.  B.  Lyons  (Pharm.  Jour.,  [3],  xvi.  880)  with  the  following 
results : — Concentrated  sulphuric  acid  dissolves  the  pure  alkaloid 
with  faint  yellow  colour,  changing  to  a  deep  blue-purple  on  heat- 
ing. If  the  reagent  contains  a  trace  of  nitric  acid  a  yellow  colour 
is  produced,  and  with  a  larger  proportion  (1:1000)  the  colour  is 
orange-red.  Pure  nitric  acid  produces  a  permanent  orange  solu- 
tion, which  on  adding  water  deposits  an  insoluble  substance,  and 
yields  a  liquid  exhibiting  an  intense  blue  fluorescence  (compare 
last  page). 

With  sulphuric  acid  and  oxidising  agents  (compare  page  368) 
hydrastine  produces  some  well-defined  colour-reactions.  With 
manganese  dioxide  an  orange  colour  is  first  developed,  changing  to 
a  rich  cherry-red,  and  passing  through  carmine  to  a  yellowish  shade 
of  red,  which  after  a  time  changes  rather  suddenly  to  a  pale  orange- 
yellow.  This  reaction  distinguishes  hydrastine  from  strychnine 
and  gelsemine,  while  berberine  dissolves  in  sulphuric  acid  with 
yellow  colour,  changing  on  addition  of  the  oxidising  agent  to  violet, 
then  to  chocolate-brown,  and  finally  becoming  orange-red.  (The 
intermediate  chocolate-brown  stage  distinguishes  the  berberine 
reaction  from  that  given  by  strychnine.)  Potassium  permanganate 
gives  with  hydrastine  and  sulphuric  acid  the  same  colorations  as 
manganese  dioxide,  but  the  changes  are  more  rapid.  A  violet  tint 
is  sometimes  produced  after  the  red  is  developed,  the  contrary  order 
being  characteristic  of  strychnine. 

Frdhde's  reagent  gives  with  hydrastine  a  sage-green  colour,  slowly 
changing  to  brownish,  and  then  gradually  fading.  This  succession 
of  tints  is  very  characteristic.  Sulphovanadic  acid  gives  a  rose- 
red  colour,  which  fades  slowly. 

On  treating  an  acid  solution  of  hydrastine  with  oxidising  agents 
{e.g.,  manganese  dioxide  and  sulphuric  acid),  it  splits  up  into 
opianic  acid  (page  298)  and  hydrastinine,  a  base  closely 
resembling  cotarnine  (page  299).     If  the  oxidation  be  efi'ected  in 

*  The  same  fluorescent  oxidation-product  is  sometimes  developed  in  solutions 
of  hydrastine  by  mere  exposure  to  air.  Neither  pure  hydrastine  nor  any  ready- 
formed  constituent  of  Hydrastis  root  appears  to  be  fluorescent. 


470  HYDRASTININE 

alkaline  solution,  the  action  proceeds  further,  the  chief  products 
being  hemipinic  (page  299)  and  nicotinic  acids  (page 
111).  This  behaviour  suggests  a  close  relationship  between  hydras- 
tine  and  narcotine,  but  hitherto  all  attempts  to  convert  one  of  these 
bases  into  the  other  have  been  unsuccessful.^ 

HYDRASTININE,  Chilli  NOg  +  HgO,  pioduced  together  with  opianic 
acid  by  the  action  of  oxidising  agents  on  hydrastine,  forms  white 
crystals,  melting  at  116°- 11 7°  C,  or  at  100°  after  heating  for 
some  time  to  that  temperature.  It  dissolves  in  water  to  form  a 
strongly  alkaline  and  very  bitter  solution.  It  is  also  soluble  in 
ether,  ethyl  acetate,  benzene,  and  petroleum  spirit,  and  crystallises 
from  each  of  these  solvents  with  1  aqua,  which,  however,  is 
eliminated  in  the  salts,  a  fact  probably  due  to  the  formation 
of  a  closed  ring.  CiiH^^NOgjIICl  crystallises  in  feebly  coloured 
needles,  soluble  in  water  and  alcohol.  The  aqueous  solution  is 
optically  inactive  and  feebly  fluorescent.  B,B[2S04  forms  yellow 
crystals  showing  a  green  fluorescence,  and  is  soluble  in  alcohoL 
Hydrastinine,  when  treated  with  aqueous  potash,  yields  hydro- 
hydrastinine,  CiiH^gNOg,  and  oxyhydrastinine, 
CiiHi^NOg.  The  latter  is  a  feeble  base,  melting  at  97°-  98°  and 
distilling  above  350°,  and  forms  crystallisable  salts.  The  former 
base  is  also  formed  by  the  action  of  reducing  agents  on  hydras- 
tinine. It  forms  white  crystals  melting  at  66°,  and  yields 
crystallisable  salts. 

When  hydrastinine  is  oxidised  in  dilute  alkaline  solution  with 
a  cold  saturated  solution  of  potassium  permanganate,  it  is  converted 
almost  quantitatively  into  oxyhydrastinine,  C^^Hj^NOg. 
Excess  of  the  oxidising  agent  and  slight  heating  carries  the  oxida- 
tion to  hydrastinic  acid,  CuHgNOg,  a  body  crystallising  in 
flat  needles  melting  at  164°,  soluble  in  alcohol  and  ether,  and 
yielding  no  precipitate  with  silver,  barium  or  lead  salts.^ 

Canadine,  C21II21NO4,  is  an  alkaloid  accompanying  berberine 
and  hydrastine  in  golden  seal  root.  Until  recently  there  was  some 
doubt  as  to  its  actual  existence,  Lloyd  having  failed  to  detect 
it  in  the  extract  from  a  very  large  quantity  of  the  root ;  but  F. 

^E.  Schmidt  considers  that  narcotine  contains  three metlioxyl  groups  and 
hydrastine  only  two,  their  formulae  being  respectively  Oi9Hi4(OMe)3N04  and 
Ci9Hi5(OMe)2N04.  As  these  bases  both  yield  on  oxidation  opianic  acid,  which 
contains  two  methoxyl  groups,  and  cotarnine  contains  one  such  group,  it 
follows  that  hydrastine  contains  no  methoxyl,  and  that  cotarnine  has  the  con- 
stitution of  a  methylated  hydrastinine. 

2  The  constitution  of  liydrastinine  and  hydrastine  has  been  the  subject  of 
various  investigations  by  Freund,  Will,  Eose,  Rosenberg,  Lachman,  Schmidt, 
Wilhelm,  Kerstein,  Heim,  Pliilips,  Dormeyer,  and  others  {Berichte,  xix.  2797; 


CANADINE — CALUMBA  ROOT.  471 

W  i  1  h  e  1  m  and  E.  Schmidt  have  independently  isolated  tho 
alkaloid,  which  is  described  as  forming  fine,  white,  shining  crystals, 
melting  at  134°,  and  more  readily  soluble  than  berberine  in  water 
and  alkalies. 

The  salts,  with  the  exception  of  the  sulphate,  are  soluble  with 
difficulty  in  water  and  alcohol.  B,HC1  and  BgjHgSO^  are  crystalline. 
By  treatment  with  iodine  in  alcoholic  solution,  canadine  is  converted 
into  the  hydriodide  of  methyl-berberine,  and  hence  it  probably  has 
the  constitution  of  a  dihydromethylene-berberine, 

Xanthopuccine  is  the  name  proposed  by  Lerchen  (1878) 
for  an  alkaloid  of  doubtful  existence  occurring  in  hydrastis.  It  is 
described  as  insoluble  in  ether  and  chloroform,  but  soluble  in 
alcohol  and  hot  water.  The  alcoholic  solution  yields  light  brown 
spangles  with  iodised  potassium  iodide. 

Indications  of  other  alkaloids  in  hydrastis  have  been  obtained 
by  A.  K.  Hale  {Tear-Book  Pharm.,  1874,  page  31)  and  J.  C. 
Burt  {ibid.,  1886,  page  95). 

Calumba,  or  Columba,^  is  the  root  of  Jateorhiza  Calumha 
or  Cocculus  palmatus,  a  herbaceous  climbing  plant  occurring  in 
the  forests  of  East  Africa. 

The  calumba  of  commerce  consists  of  dried  transverse  slices  of 
the  root.  It  possesses  mild  bitter  tonic  properties,  and  the  tincture, 
extract,  and  infusion  are  official  preparations.  The  roots  of  bryonia 
and  Frasera  Walteri  have  been  occasionally  sold  as  calumba. 

Calumba  root  contains  three  distinct  bitter  principles  in  addition 
to  starch  (35  per  cent.),  gum  (4*7),   pectin  (17),  resin,  wax,  and 

XX.  80,  2400;  xxii.  456,  1156,  2322,  2329;  xxiii.  404,  416,  2469,  2897,  2920; 
xxiv.  2730,  3164;  Arch.  Pharm.,  [3],  xxvi.  329;  xxviii.  49,  221). 

M.  Freund  {Ber.,  xxii,  2329)  suggests  the  following  structural  formulae  for 
hydrastinine  and  its  derivatives  : — 

Hydrohydrastinine,         .         .     CHgJ  q  hCgHgj  qjj'qjj     r 

Hydrastinine,  .         .         .     CHaj  q  jCsHsl  cH^.CHa     ^} 

Oxyhydrastinine,    .         .         .     CHaj  q  jCfiHaj  qjj'^  qjj®  | 
For  hydrastine  itself  Freund  suggests  the  following  formula  : — 
CH2-[Q|CeH2(CH2.CHj.NHMe).C:C.C6H2(OMe)2.COOH. 

On  decomposition  into  hydrastinine  and  opianic  acid,  fission  would  take 
place  at  the  point  of  triple  linkage,  both  the  acid  and  the  basic  derivative 
possessing  aldebydic  functions. 

^  German  :  Kalurriba  or  Columho  wurzel.     French  ;  Racine  de  Columbo. 


472  COLUMBIN. 

mineral  matter  (6  per  cent.).  Potassium  nitrate  has  been  found,  but 
not  tannin.  Berberine,  the  characteristic  yellow  alkaloid 
of  calumba  root  has  already  been  described  (page  462). 

CoLUMBiN,  or  Calumba  Bitter,  C21H22O7,  exists  in  calumba 
root  to  the  extent  of  0'34  to  0'40  per  cent.  To  extract  it,  the  material 
is  exhausted  with  boiling  alcohol,  the  extract  evaporated  to  dry- 
ness, the  residue  taken  up  with  hot  water,  and  the  filtered  liquid 
shaken  with  ether ;  or  the  tincture  is  evaporated  to  a  syrup,  and 
shaken  with  chloroform.  The  chloroform  solution  is  filtered, 
evaporated,  and  treated  with  60  per  cent,  alcohol,  which  dissolves 
most  of  the  colouring  matter.  The  residue  is  dissolved  in  strong 
alcohol,  the  solution  decolorised  with  animal  charcoal,  and  the 
columbin  crystallised.  Columbin  is  an  intensely  bitter,  inodorous, 
neutral  body.  It  melts  at  182°,  and  crystallises  from  acetic  acid 
solution  in  colourless  trimetric  prisms,  very  slightly  soluble  in  cold 
water,  more  freely  in  hot. 

Columbin  is  sparingly  soluble  in  cold  alcohol,  and  in  40  parts 
of  the  boiling  solvent.  It  dissolves  with  difficulty  in  cold  ether, 
more  readily  in  hot,  and  may  be  separated  from  berberine  by 
agitating  the  acidulated  liquid  with  this  solvent. 

The  solution  of  columbin  is  intensely  bitter ;  it  is  not  precipitated 
by  tannin  or  any  metallic  salts. 

Columbin  dissolves  in  strong  sulphuric  acid  with  orange  colour, 
changing  to  deep  red  ;  on  adding  water  brown  flakes  are  deposited. 
Columbin  dissolves  in  aqueous  alkalies,  and  is  reprecipitated  by 
acids.  On  heating  with  caustic  alkali  an  acid  body  is  formed. 
According  to  H  0  u  d  e,  columbin  produces  vomiting  and  diarrhoea. 
O'lO  gramme  was  fatal  to  a  fowl,  death  being  preceded  by  diges- 
tive disturbance  and  frequent  evacuations  {Pharm.  Jour.,  [3],  xvi. 
838). 

CoLUMBic  Acid,  CggHg^Og  +  HgO,  is  prepared  by  treating  the 
dried  alcoholic  extract  of  calumba  root  with  lime-water,  and  pre- 
cipitating the  solution  with  hydrochloric  acid.  It  is  a  yellow 
amorphous  body,  somewhat  less  bitter  than  columbin;  nearly 
insoluble  in  water,  but  little  soluble  in  ether,  more  readily  in 
acetic  acid,  and  easily  in  alcohol.  The  alcoholic  solution  precipi- 
tates lead  acetate  yellow. 


CAFFEINE  AND  ITS  ALLIES. 

Caffeine,  the  characteristic  alkaloid  of  coffee,  was  obtained 
pure  in  1821,  when  it  was  prepared  almost  simultaneously  by 
Runge,  Pelleticr  and  Caventon,  and  Robiquet.     In  1827,  Oudry 


XANTHINE  DERIVATIVES.  473 

discovered  a  similar  principle  in  tea,  and  named  it  theine. 
B  e  r  z  e  1  i  u  s  suggested  the  identity  of  this  with  caffeine,  and  this 
was  afterwards  established,  as  also  was  that  of  the  alkaloid  of 
guarana, called  by  Martins  guaranine.  Mate,  or  Paraguay 
tea,  and  Kola  nuts  contain  the  same  alkaloid,  while  cocoa  contains 
the  alkaloid  theobromine  (which  may  be  regarded  as  a  lower 
homologue  of  caffeine)  in  addition  to  small  quantities  of  caffeine. 

Unlike  the  majority  of  the  alkaloids  hitherto  described,  theo- 
bromine and  caffeine  are  not  related  to  pyridine  or  quinoline. 
They  are  respectively  the  di-  and  tri-methyl-derivatives  of  xan- 
thine, C5H4N4O2,  a  weak  base  forming  the  chief  constituent  of  cer- 
tain rarely-found  urinary  calculi,  and  existing  constantly  to  a  minute 
extent  in  normal  urine  and  in  most  of  the  organs  of  the  human 
body.  Xanthine  itself  is  closely  allied  to  u  r  i  c  acid,  Cgll^K^Og, 
from  which  it  differs  by  a  single  atom  of  oxygen,  and  from  which 
it  can  be  produced  by  treatment  wath  sodium  amalgam  and  water. 
On  adding  silver  nitrate  to  an  ammoniacal  solution  of  xanthine,  an 
amorphous  precipitate  of  the  silver-derivative,  CgHgAggN^Og, 
is  formed,  and  this  when  heated  with  methyl  iodide  is  converted 
into  dimethyl-xanthine  or  theobromine,  €5112(0113)2X402. 
When  the  silver-derivative  of  theobromine,  C5HAg( 0113)21^402, 
is  heated  with  methyl  iodide  to  160°  0.  for  twenty  hours,  trimethyl- 
xan thine  or  c  a  f  f  e  i  n  e,  C5H(CH3)3N402,  is  produced. 

The  following  formulae  show  the  constitution  of  caffeine  and 
theobromine,  and  their  relation  to  xanthine  -} — 

Xanthine,         .         .       HN OH* 

I  II 

00       0— NH 

I  I       >00* 

Theobromine,   .         .  CH3.N OH* 

I  II 

00  0— KOH3 

I        I      Noo* 

HN 0    N/ 

Caffeine,  .         .  OH3.N OH* 

1  II 

00      0— KOH3 

'         I       \oo* 

CH3.N 0=K/ 

^  The  formulae  given  in  the  text  are  those  proposed  by  Emil  Fischer 
(Annalen,  ccxv.  314).  In  the  formulse  of  M  e  d  i  c  u  s  {Annalen,  clxxv.  250), 
the  CH  and  CO  groups  marked  with  an  asterisk  are  transposed. 


474  SOURCES  OF   CAFFEINE. 

Theophijlline  (see  page  498),  a  base  isomeric  with  theobromine,  has 
been  found  in  minute  quantity  in  tea,  as  also  has  xanthine  itself.^ 

Caflfeine.^    Theine.^    Trimethyl-xanthine.   Methyl-theobromine. 
CgHioNA;  orC5H(CH3)3lsr,02. 
The  constitution  and  synthesis  of  caffeine  have  already  been  described 
(see  page  473). 

Caffeine  exists  naturally  in  the  following  sources,  all  of  which 
are  employed  for  food  or  preparing  beverages  : — 

a.  C  0  f  f  e  e ;  2  the  dried  seed  of  Goffea  Arabica. 

b.  T  e  a ;  2  the  prepared  and  dried  leaves  of  Camellia  Thea. 

c.  Mat^  or  Paraguaytea;  the  dried  leaves  and  twigs  of 
Bex  Paraguay ensis. 

d.  Guarana  or  Brazilian  chocolate;  the  dried  pulp 
of  the  seed  of  Paullinia  sorbilis. 

e.  Cola;  the  seeds  or  nuts  of  the  Kola  tree  ( Cola  or  Sterculia 
acuminata)  of  West  Central  Africa. 

Caffeine  is  found  in  other  parts  of  these  plants  besides  those 
commonly  used  for  food,  and  also  occurs  in  small  quantity,  together 
with  theobromine,  in  cocoa. 

Caffeine  can  be  isolated  with  facility  in  a  state  of  considerable 
purity,  but  its  quantitative  determination  is  attended  with  con- 
siderable uncertainty,  chiefly  owing  to  the  difficulty  of  completely 
extracting  it  from  its  natural  sources  (see  page  488). 

Caffeine  is  now  prepared  on  a  considerable  scale  from  damaged 
tea.3  Several  methods  have  been  employed  for  the  purpose,  one 
of  the  simplest  being  to  exhaust  the  tea  with  boiling  water,  boil 

^  For  the  isolation  of  xanthine  from  tea,  A.  Baginsky  extracted  the 
material  with  dilute  sulphuric  acid,  treated  the  clear  liquid  with  baryta-water 
in  excess,  and  then  passed  carbon  dioxide  to  precipitate  the  excess  of  baryta. 
After  filtering  and  evaporating,  ammonia  and  silver  nitrate  were  added,  and 
the  resultant  precipitate  of  xanthine-silver  crystallised  from  its  solution 
in  dilute  nitric  acid  to  which  some  urea  had  been  added.  The  xanthine-silver 
nitrate  obtained  contained  33 "6  per  cent,  of  Ag,  or  very  nearly  the  amount 
required  by  the  formula  C5H4N4O2,  AgNOg.  The  weight  obtained  foom  1  lb. 
of  tea  was  only  0*1567  gramme  [Pharm.  Jour.,  [3],  xix.  41). 

'  The  absolute  identity  of  the  alkaloids  of  tea  and  coffee  is  generally 
accepted,  but  cannot  be  said  to  have  been  established  absolutely  beyond  doubt. 
According  to  Lauder  Brunton  and  Cash  {Proc.  Royal  Society,  1887), 
the  physiological  effects  of  the  alkaloids  extracted  from  tea  and  coffee  exhibited 
marked  differences.  Theine  (from  tea)  appeared  to  be  more  powerful  in  its  action 
than  caffeine  (from  coffee),  and  tended  to  produce  rhythmical  contractions  of 
the  voluntary  muscles.     These  observations  have  not  been  confirmed. 

'^  A  few  years  since  the  manufacture  of  caffeine  was  almost  monopolised  by 
Germany.     In  consequence  of  a  revised  regulation  of  the  English  customs, 


CHARACTERS   OF   CAFFEINE.  475 

the  decoction  with  litharge  or  acetate  of  lead,  and  concentrate  the 
filtered  sohition  till  the  alkaloid  crystallises  out  on  cooling.  The 
product  can  be  purified  by  resublimation,  or  by  crystallisation 
from  hot  water. 

Cafi'eine  forms  long,  white,  silky,  flexible  needles,  which  readily 
felt  together  to  form  light  fleecy  masses.  When  deposited  slowly 
from  an  aqueous  or  chloroformic  solution,  the  crystals  of  cafi'eine 
present  a  characteristic  appearance  under  a  magnifying  power  of 
100  to  300  diameters. 

It  is  generally  stated  that  caffeine  crystallises  from  water  with  1 
aqua  (8*49  per  cent.),  but  the  proportion  ordinarily  present  in 
crystallised  cafi'eine  is  sensibly  less  than  corresponds  to  this  formula. 
ThusPfaff  and  Liebig  found  7-85  and  Martins  8'14  per 
cent.,  and  the  author  in  two  commercial  specimens  obtained  7*05 
and  7*10  per  cent.^  It  is  probable  that  the  deficiency  is  due  to 
efflorescence,  for  the  water  of  crystallisation  is  lost  by  prolonged 
exposure  over  concentrated  sulphuric  acid  at  the  ordinary  tem- 
perature and  pressure,  so  that  the  caffeine  so  treated  suffers  no 
further  loss  of  weight  at  100°. 

On  heating  crystallised  caffeine  to  100°  C.  the  crystals  become 
opaque  and  friable,  consequent  on  the  loss  of  water,  the  residue 
consisting  of  anhydrous  caffeine  and  dissolving  without  turbidity 
in  chloroform.  According  to  Mulder,  caffeine  is  deposited  in 
anhydrous  crystals  from  alcohol  or  ether,  and  under  certain  con- 
ditions from  water  also.  It  is  possible  that  hydration  may  depend 
on  unrecognised  conditions,  such  as  those  of  temperature  and  con- 
centration of  the  solution  at  the  time  of  separation,  and  that  com- 
mercial caffeine  is  a  variable  mixture  of  anhydrous  and  hydrated 
crystals. 

Caffeine  does  not  evaporate  with  vapour  of  water,  and  undergoes 
no  appreciable  change  of  weight  at  100°  (A.  H.  Allen).^  At 
120°  it  volatilises  very  gradually,  and  at  a  higher  temperature 
sublimes  unchanged  in  long,  silky  needles. 

according  to  which  damaged  tea  is  admitted  duty-free,  provided  that  it  be 
*'  denatured"  and  rendered  wholly  unfit  for  human  consumption  by  treatment 
with  lime  and  assafcetida,  it  has  become  possible  to  use  such  tea  profitably  for 
the  manufacture  of  caffeine.  As  a  result,  England  has  become  the  chief  seat 
of  the  manufacture,  and  now  exports  the  alkaloid  to  Germany  and  America. 
At  present  (August,  1892)  the  retail  price  of  caffeine  from  tea  is  9d.  per  ounce. 

^  Mulder  found  8  "49  per  cent,  of  water,  but  that  was  by  exposing  the 
substance  to  a  temperature  above  120°,  when  more  or  less  volatilisation  must 
have  taken  place. 

2  The  statements  respecting  the  effect  of  heat  on  caffeine  are  very  discordant. 
According  to  A.  Wynter  Blyth,  caffeine  sublimes  in  minute  needles  at 


476 


CHARACTERS   OF  CAFFEINE. 


At  23r-233°  C.  cafifeine  melts  to  a  clear  liquid,  and  at  384° 
(S  t  r  e  c  k  e  r)  boils  and  distils  with  partial  decomposition,  leaving 
no  residuum. 

79°  C,  and  volatilises  completely  at  120°.     Other  observers  give  much  higher 
temperatures  for  its  subliming  point. 

The  behaviour  of  caffeine  when  heated  has  an  important  bearing  on  the 
methods  of  determining  the  alkaloid,  and  hence  has  recently  been  carefully 
re-investigated  in  the  author's  laboratory  by  G.  E.  Scott  Smith,  C.  M.  Caines, 
and  G.  S.  A.  Caines.     The  following  facts  have  been  fully  established  : — 

1.  Commercial  caffeine  (crystallised)  lost  6*9  per  cent,  of  its  weight  by 
prolonged  drying  over  concentrated  sulphuric  acid  at  the  ordinary  temperature 
and  pressure. 

2.  Caffeine  which  has  been  dried  at  the  ordinary  temperature  over  sulphuric 
acid  till  constant  in  weight  undergoes  no  further  material  loss  on  prolonged 
exposure  in  an  open  dish  in  the  water-oven  at  100°.  The  following  results 
were  obtained  : — 


Caffeine. 

Loss. 

Weight  of  commercial  alkaloid  taken, 

1-000  gramme. 

... 

„       after  long  exposure  over  H2SO4  at  20°  C, 

0-931 

6-9  per  cent. 

„       after  heating  in  water-oven  for  2J  hours, 

0-929       „ 

71       „ 

II                             II                                        l>                         "5          II 

0-929        „ 

7-1       II 

51        „ 

0-927        „ 

7-3       „ 

3.  Notwithstanding  the  foregoing  results,  on  heating  caffeine  contained  in  a 
watch-glass,  covered  with  another  watch-glass,  over  boiling  water  or  on  the  top 
of  the  water-oven  for  fifteen  minutes,  a  distinct  film  appeared  on  the  covering 
glass,  and  crystals  of  caffeine  were  observable  under  the  microscope.  The 
slight  loss  of  weight  observed  when  caffeine  was  exposed  for  many  hours  at 
100°  is  doubtless  due  to  volatilisation. 

4.  On  exposing  dry  caffeine  to  a  temperature  of  120°  in  an  air-bath,  a  very 
gradual  but  continual  decrease  of  weight  was  observed,  indicating  sensible 
volatilisation  of  the  alkaloid  at  the  temperature  employed.     Thus  : — 


Weight  of  Alkaloid. 

Loss. 

Grammes. 

Grammes. 

Per  cent. 

Moisture-free  caffeine  taken, 

0-9290 

... 

After  heating  for  2  hours  at  120% 

0-9260 

0-0030 

0-32 

6     „ 

0-9270 

0-0220 

2-37 

11     „ 

0-8668 

0  0622 

6-69 

14      1, 

0-8314 

0-0976 

10-50 

17     .1 

0-7850 

0-1440 

15-50 

II           20     „          „ 

0-7654 

01536 

16-53 

24      „ 

0-7568 

0-1722 

18-53 

i>          t>           29     „          „ 

0-7486 

0-1804 

19-42 

CHARACTERS   OF   CAFFEINE.  477 

Caffeine  is  odourless,  but  has  a  bitter  taste.  It  has  a  marked  phy- 
siological action,  and  in  excessive  doses  possesses  decided  poisonous 
properties.  Administered  to  frogs,  it  produces  tetanus  and  rigor 
of  the  voluntary  muscles.  A  cat  was  killed  in  thirty-five  minutes 
by  administering  J  gramme  of  alkaloid.  In  all  experiments  with 
caffeine  on  the  lower  animals  there  has  been  increased  frequency 
of  the  heart's  action,  and  repeated  emptying  of  the  bladder  and 
intestines.  After  death,  the  alkaloid  has  been  detected  in  the 
blood,  the  bile,  and  the  urine.  In  man,  caffeine  increases  the 
heart's  action,  by  stimulating  the  cardiac  muscles,  and  excites  the 
nervous  system. 

The  British  Pharmacopoeia  gives  from  1  to  5  grains  as  the 
medicinal  dose  of  caffeine ;  the  German  Pharmacopoeia  states  the 
maximum  single  dose  at  0*2  gramme,  and  the  daily  maximum  dose 
at  0"6  gramme. 

The  physiological  action  of  infusions  of  tea  and  coffee  is  in 
part  due  to  the  caffeine,  but  is  largely  modified  by  the  other 
constituents;  notably  the  tannin,  extractive  matter,  and  pos- 
sibly the  essential  oil  of  tea,  and  the  catfeol  or  essential  oil  of 
coffee. 

Caffeine  is  only  sparingly  soluble  in  cold  water  (75  to  80  parts), 
but  tolerably  readily  in  hot  (10  parts).  It  dissolves  in  about  35 
parts  of  cold  rectified  spirit,  but  it  is  much  less  soluble  (1  :  155) 
in  absolute  alcohol.  In  cold  ether  it  is  very  sparingly  soluble, 
more  readily  in  amylic  alcohol,  chloroform  and  benzene,  but  nearly 

5.  Caffeine  which  had  been  recently  sublimed  and  was  consequently 
anhydrous,  melted  at  231  -6°  C. ,  and  resolidified  at  223°  C.  Strecker  gives 
the  melting-point  of  anhydrous  caffeine  as  234°,  and  Biedermann  at 
230*5°.  Mulder  gives  the  melting-point  at  177 "8°,  which  is  certainly  too 
low. 

6.  Caffeine  which  had  been  recently  sublimed  and  then  dissolved  in  water, 
alcohol,  ether  or  chloroform,  in  each  case  left  the  original  weight  of  alkaloid 
on  evaporating  the  solution  and  exposing  the  residue  at  100°.  The  same 
result  was  obtained  with  recently-fused  caffeine.  As  sublimed  and  fused 
caffeine  are  certainly  anhydrous,  it  follows  that  the  alkaloid  left  on  evaporat- 
ing its  solutions  in  the  above  solvents  is  also  anhydrous. 

7.  When  a  known  weight  of  caffeine  was  repeatedly  treated  with  a  small 
quantity  of  water,  and  the  liquid  evaporated  to  dryness  at  100°,  the  original 
weight  was  always  recovered.  When  caffeine,  previously  dried  at  100°  or 
120°,  or  recently  sublimed  or  fused,  was  dissolved  in  1000  parts  of  distilled 
water,  the  solution  concentrated  by  boiling  over  a  naked  flame,  and  the 
evaporation  completed  in  a  platinum  dish  at  100°,  the  residue  being  finally 
dried  in  the  water-oven,  the  weight  of  alkaloid  originally  taken  was  strictly 
recovered.  This  proves  that  caffeine  does  not  volatilise  with  steam  during  the 
evaporation  of  its  solutions  (A.  H.  Allen,  Pharm.  Jour.,  [3],  xxiii.  213). 


478 


DECOMPOSITION -PRODUCTS   OF   CAFFEINE. 


iQSoluble  in  carbon  disulphide  and  petroleum  spirit.^  Chloroform 
and  benzene  dissolve  out  the  alkaloid  even  from  its  acidulated 
aqueous  solutions,  but  the  agitations  must  be  several  times  repeated 
to  effect  complete  extraction. 

Concentrated  sulphuric  acid  converts  caffeine  into  the  sulphate, 
but  does  not  colour  or  otherwise  change  it  even  at  100°  C.^ 

Hydrochloric  acid  has  no  action  on  caffeine  below  200°,  but 
when  heated  under  pressure  with  concentrated  hydrochloric  acid  to 
250°  for  six  to  twelve  hours  caffeine  yields  ammonia,  methylamine, 
sarcosine,  carbon  dioxide,  and  traces  of  formic  acid.  The  volume 
of  methylamine  produced  is  double  that  of  the  ammonia,  which 
proves  the  presence  of  three  NMe  groups  in  caffeine,  and  estab- 
lishes the  following  formula  for  the  reaction: — C8H^o^^^^2  + 
6H2O  ^  NH3  +  2N(CH3)H2  +  C3H7NO2  -f  CH2O2  +  CO2  (K 
Schmidt,  Annalen,  ccxvii.  270).^ 

When  caffeine  is  warmed  with  dilute  caustic  alkali  or  boiled  with 
concentrated  baryta-water,  it  at  first  assimilates  the  elements  of 

^  A.  Coramaille  {Compt.  Bend.,  cxxxi.  817  ;  Jour.  Chem.  Soc.  xxix.  779) 
gives  the  following  figures  for  the  solubility  of  hydrated  and  anhydrous  caffeine 
in  different  menstma :  — 


Parts  of  Solvent  required  for  1  of  Caffeine. 

Solvent. 

At  15°  to  17°  C. 

At  Boiling- 
point  of 
Solvent.* 

Hydrated.    |  Anhydrous.  |   Anhydrous. 

Water, 

Rectified  spirit,      . 
Absolute  alcohol,    . 
Commercial  ether, 
Pure  anhydrous  ether, 
Chloroform,  . 
Carbon  disulphide, 
Petroleum  ether,    . 

68 
40 

476 

74 
44 
165 
526 
2288 

7-7 
1709 
4000 

2-2 
32 

277 

H 
220 

*  The  hot  water  was  at  65°  only,  not  at  the  boiling-point. 

^  Experiments  by  the  author  showed  that  pure  catfeiue  was  wholly  unchanged 
when  heated  in  the  water-oven  for  several  hours  with  concentrated  sulphuric 
acid.  On  dissolving  the  product  in  water,  boiling  with  oxide  of  lead,  filtering, 
concentrating,  and  extracting  with  chloroform,  the  original  weight  of  caffeine 
was  recovered.  Some  samples  of  commercial  caffeine  darken  slightly  when 
heated  with  sulphuric  acid. 

3  Schmidt  thought  it  possible  that  theobromine  might  be  formed  in  this 
reaction  by  the  elimination  of  a  methyl-group,  but  was  not  able  to  detect  it. 
The  methylamine  was  separated  and  purified  by  conversion  into  the  chloro- 
platinate.     The  sarcosine  was  identified  by  means  of  its  copper  salt. 


CAFFEIDINE.  479 

water  and  is  converted  into  an  acid  containing  CsH^gN^Og.^  On 
further  treatment,  this  body  splits  up  with  great  facility  into 
carbon  dioxide  and  the  base  caffeidine,  CyHjgN^O.^  On  still 
further  boiling  with  the  alkali  this  is  again  decomposed  with  forma- 
tion of  carbon  dioxide,  formic  acid,  ammonia,  methylamine,  and 
sarcosine  (methyl-amidoacetic  acid). 

The  author  has  proved  that  caffeine  readily  undergoes  decom- 
position when  boiled  with  lime-water,  a  fact  which  has  a  practical 
bearing  on  several  of  the  published  processes  for  its  determination. 
When  caffeine  is  boiled  with  magnesia  and  water,  the  decomposi- 
tion is  insignificant,  and  with  litharge  there  is  no  change. 

^  Caffeidine-carboxylic  Acid,  C8HioN403,  or  C7H11N4O.COOH,  is  best 
prepared  by  digesting  finely-divided  caireiue  for  some  hours  at  30°  C.  iu  a  dilute 
solution  of  caustic  potash  or  soda,  neutralising  with  acetic  acid,  adding  cupric 
acetate  (avoiding  excess),  and  decomposing  the  resultant  precipitate  by  sul- 
phuretted hydrogen.  The  libeiated  acid  obtained  on  evaporation  of  the 
filtrate  in  vacuo  at  the  ordinar}'  temperature,  may  be  purified  by  solution  in 
chloroform  and  precipitation  with  benzene,  and  is  thus  obtained  in  the  form 
of  a  thick  oil,  which  ou  exposure  to  the  air  solidifies  to  a  yellowish-white, 
slightly  crystalline  mass,  very  soluble  in  water  to  a  strongly  acid  liquid.  It 
is  soluble  in  alcohol  and  chloroform,  but  insoluble  iu  benzene.  On  boiling 
the  aqueous  solution  of  caffeidine-carboxylic  acid,  carbon  dioxide  is  evolved  and 
a  reddish  oil  remains,  which  when  stirred  up  wiili  a  small  quantity  of  sulphuric 
acid  and  treated  with  alcohol  solidifies  to  a  white  crystalline  mass  of  caffeidine 
sulphate.  The  reaction  affords  a  ready  method  of  prejiariug  caffeidine.  It 
IS  merely  necessary  to  decompose  the  copper  salt  with  sulphuretted  hydrogen, 
evaporate  the  filtrate  rapidly,  and  treat  it  with  strong  sulphuric  acid.  The 
copper  salt  of  caffeidine-carboxylic  acid,  Cu(CioHiiN403)2,  is  a  pale  blue 
crystalline  powder,  nearly  insoluble  in  water  and  wholly  so  in  alcohol.  The 
barium,  calcium,  zinc,  cadmium,  and  magnesium  salts  are  nearly  insoluble 
in  water,  but  the  lead  salt  is  soluble.  KA  is  a  yellow  oil.  On  adding 
mercuric  chloride  to  the  solution  of  a  soluble  caffeidine-carboxylate,  a  copious 
white  precipitate  is  obtained  which  appears  to  contain  (CgHiiN'403)2Hg,2HgC1.2. 
If  this  be  sus])ended  in  water  and  decomposed  with  sulphuretted  hydrogen, 
the  filtered  liquid  leaves  caffeidine  hydrochloride  on  evaporation. 

2  Caffeidine,  C7H12N4O,  may  be  obtained  as  above  described,  or  may  be 
prepared  by  boiling  caffeine  with  a  solution  of  10  parts  of  crystallised  baryta 
for  half  an  hour,  or  until  ammonia  and  methylamine  begin  to  be  evolved. 
From  the  product  of  the  reaction,  caffeidine  sulphate,  BH2SO4,  is  obtained  by 
acidulating  the  filtered  liquid  with  dilute  sulpliuric  acid,  and  evaporating  the 
filtrate  to  a  thin  syrup,  when  the  salt  is  deposited  in  readily  soluble  needles. 
The  free  base  is  an  oily,  strongly  alkaline  liquid,  readily  soluble  in  water, 
alcohol  and  chloroform,  but  with  difficulty  in  ether.  It  reduces  silver  oxide, 
even  in  the  cold,  and  decomposes  very  readily  into  ammonia,  methylamine, 
and  cholestrophane  (dimethylparabanic  acid),  CgHoMe.^NgOg.  Caffeidine 
nitrate,  hydrobromide,  and  hydrochloride  crystallise  well.  B.^HaPtClg crystal- 
lises from  water  in  large  orange-yellow  needles,  containing  either  2  or  4  aqua. 


480  MUREXOiN  TEST. 

When  caffeine  is  heated  with  soda-lime  to  180*',  ammonia  is 
evolved,  and  carbonate  and  a  large  quantity  of  cyanide  formed. 
According  to  Rochleder  this  last  product  distinguishes  caffeine 
from  piperine,  morphine,  quinine,  and  cinchonine.  When  caffeine  is 
ignited  with  excess  of  soda-lime,  the  nitrogen  is  evolved  as  ammonia, 
any  cyanide  formed  as  an  intermediate  product  at  a  lower  temperature 
being  decomposed  in  the  usual  manner;  but  in  order  to  ensure  com- 
plete conversion  of  the  nitrogen  into  ammonia,  it  is  better  to  mix  the 
caffeine  with  about  twice  its  weight  of  cane-sugar  (A.  H.  Allen). 

When  caffeine  is  treated  with  bromine-water,  avoiding  excess, 
and  the  liquid  evaporated  to  dryness  at  100°,  a  yellowish  residue  is 
left,  which  becomes  crimson-red  on  further  heating,  and  is  turned 
a  magnificent  purple  by  ammonia.  The  reaction  is  very  delicate, 
and  is  not  affected  by  a  considerable  excess  of  ammonia.  On 
adding  caustic  soda  complete  and  instant  decolorisation  occurs. 

Another  modification  of  the  test  consists  in  treating  a  minute 
quantity  of  the  solid  substance  (such  as  a  residue  of  caffeine  left  on 
evaporation)  in  a  porcelain  dish  with  a  few  drops  of  strong  hydro- 
chloric acid  and  a  minute  crystal  of  potassium  chlorate,  and  evapo- 
rating the  liquid  to  dryness  at  100°.  When  cold,  the  reddish-yellow 
or  pinkish  residue  is  cautiously  moistened  with  ammonia,  avoiding 
an  excess,  when  the  characteristic  purple  coloration  is  produced ;  or, 
preferably,  it  is  exposed  to  ammoniacal  vapours  by  inverting  the 
dish  bearing  the  residue  over  another  containing  strong  ammonia. 

The  products  of  the  oxidation  of  caffeine  include  a  m  a  1  i  c 
a  c  i  d,^  which  by  subsequent  treatment  with  ammonia  is  converted 
into  murexoin;  the  reactions  being  identical  to  the  eye  and 
parallel  in  chemical  change  to  those  yielded  by  uric  acid  under  like 
conditions.     Thus :  — 

Uric  acid  yields       Caffeine  yields 
With  the  oxidising  agent,   .     Alloxantin.  A  malic  acid. 

CgHeNA  C8H,(CH3)4N408 

On  adding  ammonia, .     .     .      Murexide.  Murexoin. 

NH4.  CsB.-N.O,  NH4.  CsCCHa)^^^©^ 

Strong  nitric  acid  may  be  substituted  for  the  bromine-water  or 
liydrochloric  acid  and  potassium  chlorate ;  but  the  reaction  is  in 
that  case  far  less  distinct  and  easy  to  regulate,  and  excess  of  am- 
monia must  be  carefully  avoided.^ 

^  Amalic  Acid  forms  colourless  crystals  which  stain  the  skin  red,  and  are 
very  sparingly  soluble  in  water  or  alcohol.  It  reduces  silver  salts,  and  forms 
deep  violet  compounds  with  potash,  soda,  and  baiyta. 

'^  0.  H  eh  n  er,  in  a  private  communication  to  the  author,  points  out  that, 
if  the  nitric  acid  used  be  perfectly  pure,  caffeine  fails  to  give  the  murexoin 
reaction,  but  that  in  presence  of  a  minute  trace  of  hydrochloric  acid  the  coloui 
is  readily  developed. 


REACTIONS  OF  CAFFEINE.  481 

Theobromine  and  xanthine  give  similar  reactions  to  caffeine  with 
an  oxidising  agent  and  ammonia.  The  purple  colorations  due  to 
caffeine  and  theobromine  are  decolorised  by  adding  caustic  alkali 
solution,  but  that  due  to  uric  acid  is  changed  to  blue. 

When  caffeine  is  heated  with  a  large  excess  of  nitric  acid,  it  is 
converted  into  cholestrophane^  or  dimethylparabanic 
acid,  C3(CH3)2]Sr203,  a  body  which  crystallises  in  pearly  laminae, 
melting  at  145-5°,  boiling  at  275°-277°,  and  difficultly  soluble 
in  cold  water  and  alcohol.  It  is  decomposed  with  great  facility 
by  alkalies  into  symmetrical  dimethylurea  (melting  at 
97°-100°)  and  oxali  c  acid.  Hence  on  adding  ammonia  and 
calcium  chloride  to  its  aqueous  solution,  and  warming  the  liquid, 
calcium  oxalate  is  precipitated. 

Cholestrophane  is  also  produced  (35"4  to  41*8  per  cent.)  by 
oxidising  caffeine  with  chromic  acid  mixture,  the  main  reaction 
being : — 

C5H(CH3)3N402  +  O3  +  2H,0  »  C3(CH3)2N20,  +  NH2(CH3)  +  NH3  +  2CO2 . 

Caffeine  is  very  imperfectly  precipitated  by  the  usual  alkaloidal 
reagents.  No  reactions  result  with  iodised  potassium  iodide  and 
Mayer's  solution,  which  behaviour  distinguishes  caffeine  from  nearly 
all  other  alkaloids  except  theobromine  and  colchicine.  Potassio- 
bismuth  iodide  precipitates  caffeine  after  a  time  from  moderately 
dilute  solutions  (1  :  3000).  Phosphomolybdic  acid  produces  a 
yellowish  precipitate,  soluble  in  warm  sodium  acetate  solution,  the 
liquid  depositing  free  caffeine  on  cooling.  (C8HjQN'402.HCl)2PtCl4 
is  obtained  on  adding  hydrochloric  acid  and  platinic  chloride  to  a 
highly  concentrated  solution  of  caffeine,  as  an  orange  precipitate 
soluble  in  20  parts  of  cold  and  an  even  smaller  quantity  of  warm 
water,  crystallising  again  on  cooling. 

A  solution  of  caffeine  in  200  parts  of  water  gives  an  immediate 
and  abundant  precipitate  on  adding  a  saturated  solution  of  mercuric 
chloride.  With  a  more  dilute  solution  (1  :  1000)  crystals  appear 
in  a  few  minutes,  and  in  an  hour  or  two  an  abundant  crop  of  large 
acicular  crystals  is  obtained.  With  a  solution  of  caffeine  in  4000 
of  water  crystals  appear  after  a  few  days.  The  precipitate  con- 
tains C8HjQN402,HgCl2,  and  is  much  less  soluble  in  excess  of  the 
reagent  than  in  pure  water.  Hence  the  best  results  are  obtained 
by  adding  an  equal  measure  of  a  concentrated  solution  of  mercuric 
chloride  to  the  liquid  to  be  tested.  The  compound  is  soluble  in 
about  260  parts  of  cold  water,  and  more  readily  in  hot,  crystallising 
out  again  on  cooling.     It  also  crystallises  from  hot  alcohol.     The 

^  The  name  cholestrophane  is  due  to  Stenhouse,  and  has  reference  to 
the  resemblance  the  crystals  have  tocholesterin  (Vol.  II.  page  312). 
VOL.  III.  PART  II.  2  H 


482  SALTS   OF   CAFFEINE. 

compound  is  not  sufficiently  insoluble  to  be  applicable  to  the 
quantitative  precipitation  of  caffeine  (R.  H.  D  a  v  i  e  s,  Pharm.  Jour.^ 
[3],  xxi.  253). 

Gallotannic  acid  precipitates  moderately  dilute  solutions  of 
caffeine,  the  precipitate  being  somewhat  soluble  in  excess  of  the 
reagent.  A  difference  of  a  few  degrees  in  temperature  greatly 
alters  the  solubility,  and  hence  a  solution  of  properly  adjusted 
strength  may  be  perfectly  limpid  at  one  temperature,  and  become 
completely  opaque  from  separation  of  amorphous  caffeine  gallo- 
tannate  on  cooling  a  few  degrees.  A  similar  separation  of  caffeine 
tannate  is  the  cause  of  an  infusion  of  tea  becoming  turbid  on 
cooling. 

Salts  of  Caffeine. 

Caffeine  is  a  very  feeble  base.  Its  aqueous  and  alcoholic  solu- 
tions have  no  action  on  litmus,  and  it  is  extracted  from  aqueous 
liquids  by  benzene  and  chloroform,  even  in  presence  of  a  free 
mineral  acid.  This  behaviour  is  doubtless  due  to  the  facility  with 
which  the  majority  of  caffeine  salts  are  decomposed  on  dilution. 
They  are  decomposed  by  alcohol  and  ether  as  by  water,  and  the 
salts  with  volatile  acids  (e.^.,  acetic)  are  decomposed  on  exposure 
to  air.  The  hydrochloride  leaves  merely  free  caffeine  on  exposure 
to  100°  C.  The  author  found  that  on  adding  free  caffeine  to  hot 
water  containing  a  trace  of  sulphuric  acid  and  coloured  with  methyl 
orange,  the  red  colour  of  the  liquid  was  immediately  destroyed, 
proving  neutralisation  of  the  acid ;  but  an  acid  reaction  was  re- 
established when  standard  acid  had  been  added  equivalent  to  only 
about  ^  of  the  caffeine  present.  Owing  to  these  facts,  certain 
devises  have  to  be  employed  for  the  preparation  of  the  majority 
of  the  salts  of  caffeine.  The  oxalate  ^  and  salicylate  are  sparingly 
soluble,  and  can  be  readily  prepared  by  mixing  equivalent  quantities 
of  the  acid  and  alkaloid  in  aqueous  solution.  The  citrate  is  best 
obtained  by  mixing  a  chloroformic  solution  of  caffeine  with  an 
alcoholic  solution  of  citric  acid,  and  evaporating  the  mixture  to  a 
syrup.  "When  molecular  proportions  of  caffeine  and  a  mineral  acid 
are  mixed  together  in  presence  of  excess  of  water,  no  combination 
ensues.  If  the  quantity  of  water  is  insuihcient  to  dissolve  the 
alkaloid,  the  latter  remains  suspended  in  the  liquid  in  an  unchanged 
condition.  If  the  liquid  is  allowed  to  evaporate  spontaneously, 
the  acid  ultimately  becomes  sufficiently  concentrated  to  act  on  a 
portion  of  the  caffeine,  and  a  true  salt  crystallises  out,  intermingled 

1  Caffeine  oxalate  is  said  by  Leipen  to  be  an  exceptionally  stable  salt.  It 
can  be  recrystallised  from  water ;  but  the  author  found  that  the  whole  of  the 
cafifeine  could  be  removed  by  chloroform  from  an  aqueous  solution  containing  a 
considerable  excess  of  oxalic  acid. 


SALTS  OF   CAFFEINE.  483 

with  crystals  of  the  unaltered  alkaloid.  But  as  the  acid  is  weakened 
by  its  combination,  the  formation  of  the  salt  is  retarded  till  further 
concentration  has  taken  place.  Hence  the  change  is  progressive 
and  continuous,  the  caffeine  gradually  dissolving  and  again  crystal- 
lises out  as  a  salt,  though  at  the  very  last  crystals  of  the  uncombined 
base  can  be  observed  in  admixture  with  the  increasing  crop  of  the 
true  salt.  By  employing  a  considerable  excess  of  acid  the  process 
is  greatly  hastened,  and  a  product  free  from  uncombined  alkaloid 
is  obtainable.  With  an  excess  of  acid,  and  at  a  sufficient  degree 
of  concentration,  the  alkaloid  will  momentarily  dissolve  to  a  clear 
solution,  and  then  almost  immediately  crystallise  out  as  salt. 

The  foregoing  observations  are  due  to  H.  W.  Snow  (Pharm. 
Jour.,  [3],  xxi.  1185),  who  gives  the  following  as  the  composition 
of  the  principal  salts  of  caffeine  : — 

Caffeine  hydrochloride,  .  .  B,HC1  +  2H20 

Caffeine  hydrobromide,  .  .  B,HBr  +  2H20 

Caffeine  nitrate, .          .  .  .  5(B,H]Sr03)  +  H20 

Caffeine  sulphate  (normal),  .  .  B.HgSO^ 

Caffeine  oxalate,           .  .  .  B2,H2C204 

Caffeine  salicylate,  .  .  B,HC7H503 

Caffeine  hydrochloride  crystallises  in  colourless  prismatic  needles. 
It  loses  the  whole  of  its  acid  at  75°  C.  The  sulphate  is  deposited 
from  a  hot  alcoholic  solution  in  shining  needles  unchanged  at  100°. 
Caffeine  nitrate  forms  fine  transparent  crystals,  which  when  dropped 
into  water  become  opaque,  and  are  converted  into  pseudomorphs 
consisting  of  microscopic  needles  of  free  caffeine. 

Caffeine  citrate  is  official  in  the  British  Pharmacopoeia  of  1885, 
where  the  formula  C^-^^ fi^^^G^fiyj  is  ascribed  to  it.  The 
B.P.  article  is  generally  regarded  as  an  indefinite,  unstable,  in- 
accurately described,  and  superfluous  preparation  {Pharm.  Jour.^ 
[3],  xix.  252).  Free  caffeine  has  not  unfrequently  been  sold  as  the 
citrate.  The  proportion  of  acid  can  be  directly  ascertained  in 
the  citrate  and  other  caffeine  salts  by  titrating  the  solution  with  a 
standard  caustic  alkali  (or  preferably  baryta)  and  phenolphthalein, 
and  the  total  caffeine  can  be  isolated  by  agitating  the  neutralised 
or  original  aqueous  solution  with  chloroform.  On  treating  the  dry 
substance  with  cold  chloroform,  only  the  uncombined  caffeine,  if 
any,  will  be  dissolved  out  (J.  U.  L 1  o  y  d). 

A  strong  and  stable  solution  of  caffeine  can  be  readily  prepared 
by  dissolving  it  in  benzoate,  cinnamate,  or  salicylate  of  sodium  or 
ammonium.  Such  solutions  are  employed  for  hypodermic  injec- 
tions, and  caffeine  phenate  and  phthalate  have  been  applied  to  the 
same  purpose. 


ib4  ISOLATION   OF   CAFFEINE. 

Isolation  and  Determination  of  Caffeine. 

Kone  of  the  compounds  of  caffeine  are  sufficiently  stable  or 
insoluble  to  be  of  service  for  the  separation  or  precipitation  of  the 
alkaloid,  which  is  always  determined  by  weighing  it  in  the  free 
state.  The  isolation  of  caffeine  presents  no  difficulty,  and  may  be 
effected  by  a  variety  of  methods.  The  majority  of  these  depend 
on  the  treatment  of  the  substance  or  its  m^ueous  infusion  with 
lime,  magnesia,  litharge,  or  basic  lead  acetate,  to  render  the  tannin, 
&c.,  insoluble ;  and  crystallisation  of  the  caffeine  from  the  concen- 
trated filtrate,  or  extraction  of  it  by  benzene,  ether,  or  chloroform. 
To  ensure  the  absence  of  inorganic  salts,  the  alkaloid  should  be 
sublimed  or  shaken  out  from  its  aqueous  solution  by  chloroform. 
Provided  that  the  caffeine  isolated  be  well  crystallised,  colourless, 
free  from  acid  or  alkaline  reaction  to  litmus,  completely  soluble  in 
chloroform,  exerts  no  reducing  action  on  Fehling's  solution,  and 
leaves  no  ash  on  ignition,  it  may  be  regarded  as  pure. 

Although  tlie  isolation  of  caffeine  in  a  state  of  absolute  purity 
may  be  easily  effected,  the  accurate  determination  of  the  propor- 
tion of  alkaloid  present,  especially  in  tea,  is  attended  with  great 
difficulty,  and  hence  most  of  the  published  results  represent  the 
proportion  of  caffeine  isolated,  rather  than  the  amount  existing  in 
the  substance  examined.  When  once  in  solution,  several  methods 
may  be  used,  though  even  in  this  case  some  of  the  published  pro- 
cesses give  results  which  are  very  gravely  wide  of  the  truth.  As  a 
consequence,  the  great  majority  of  the  published  determinations  of 
caffeine  are  completely  worthless,  and  even  where  a  number  of 
figures  have  been  obtained  by  the  same  process  they  do  not 
necessarily  bear  any  definite  relation  to  each  other. 

The  determination  of  the  alkaloid  in  tea  has  recently  been  the 
subject  of  a  very  large  number  of  experiments  in  the  author's 
laboratory  by  C.  M.  Caines,  G.  S.  A.  Caines,  and  G.  E.  Scott  Smith 
(Pharm.  Jour.,  [3],  xxiii.  215).  The  following  facts  have  been 
fully  established : — 

1.  Aqueous  solutions  of  caffeine,  even  when  very  dilute,  may 
be  concentrated  by  boiling,  and  subsequently  evaporated  to  dry- 
ness at  100°  without  the  least  loss  of  alkaloid  (see  page  477). 

2.  Caffeine  may  be  completely  dehydrated  at  100°  in  the  water- 
oven.  It  undergoes  no  appreciable  loss  by  volatilisation  when 
exposed  to  100°  for  many  hours;  but  sublimation  to  a  minute 
extent  can  be  proved  by  the  aid  of  the  microscope  (see  page  476). 

3.  Caffeine  cannot  be  estimated,  even  approximately,  by  crystal- 
lisation from  water,  the  amount  which  remains  obstinately  in  solu- 
tion, in  the  presence  of  saline  matters,  often  exceeding  that  which 
can  be  separated  as  crystals. 


EXTRACTION   OF   CAFFEINE.  485 

4.  Cali'eine  can  be  comi)letely  extracted  from  its  acidulated  or 
slightly  anmioniacal  aqueous  solutions  by  repeated  agitation  with 
chloroform.  In  the  author's  experiments,  from  a  solution  slightly 
acidulated  with  sulphuric  acid,  the  first  treatment  with  chloroform 
extracts  from  70  to  85  per  cent,  of  the  total  alkaloid.  Four 
treatments  with  chloroform  usually  effect  the  complete  extraction 
of  the  alkaloid;  but  it  is  desirable  to  agitate  a  fifth  time  and 
evai)orate  the  separated  solvent  apart,  to  prove  that  no  more 
caffeine  is  being  dissolved.  In  this  last  case,  the  solution  may  be 
advantageously  rendered  ammoniacal,  or  a  loss  of  O'OOl  to  0*002 
gramme  of  cafieine  may  occur,  probably  owing  to  the  existence  of 
traces  of  caffeine  sulphate,  especially  where  the  solution  is  strongly 
acidulated  with  sulphuric  acid.  On  distilling  the  chloroformic 
solution  of  caffeine,  and  drying  the  residue  at  100°  C,  the  alkaloid 
is  obtained  in  a  perfectly  anhydrous  condition. 

5.  Charcoal  cannot  be  employed  for  decolorising  caffeine  solu- 
tions, without  a  considerable  absorption  of  alkaloid,  which  is 
retained  with  extreme  persistency.  If  the  caffeine  isolated  be 
coloured,  it  may  be  dissolved  in  a  little  hot  water,  and  the  filtered 
solution  evaporated  to  dryness;  but  there  is  little  difficulty  in 
isolating  the  alkaloid  in  a  snow-white  condition. 

6.  Caffeine  is  completely  unchanged  by  heating  to  100°  with 
strong  hydrochloric  acid,  or  with  sulphuric  acid  diluted  with  one- 
third  of  its  measure  of  water.  On  treating  the  mixture  with 
water,  the  whole  of  the  alkaloid  may  be  recovered  by  agitation 
with  chloroform,  as  in  4. 

7.  Caffeine  is  readily  decomposed  by  alkalies.  By  warming 
with  dilute  caustic  soda,  it  easily  undergoes  change,  and  by  boil- 
ing with  lime  it  is  partly  decomposed,  with  formation  of  ammonia 
and  methylamine  (see  page  479). 

8.  When  commercial  caffeine  is  treated  with  ignited  magnesia 
and  water,  and  the  mixture  distilled,  a  sHght  but  distinct  formation 
of  ammonia  is  observed,  apparently  accompanied  with  traces  of 
volatile  amines.  But  the  volatile  bases  are  found  chiefly  in  the 
first  fractions  of  the  distillate,  the  latter  portions  being  quite  free 
from  alkaline  reaction;  and  when  carefully  purified  caffeine  is 
employed,  the  formation  of  ammonia  and  other  volatile  bases  is 
reduced  to  a  minute  trace.  Hence  tlieir  formation  is  more  probably 
due  to  the  decomposition  of  some  impurity  present  in  small 
quantity  than  of  the  caffeine  itself,  as  in  the  latter  case  the  pro- 
duction would  continue  throughout  the  distillation.  On  filtering 
from  the  magnesia  and  extracting  the  filtrate  with  chloroform, 
the  original  weight  of  caffeine  can  be  recovered,  if  the  pure  alkaloid 
was  originally  employed. 


486  DETERMINATION   OF   CAFFEINE. 

9.  If  a  mixture  of  caffeine  with  magnesia  be  made  into  a  paste 
with  water  and  dried,  the  alkaloid  can  be  wholly  extracted  from 
the  mixture  by  prolonged  treatment  with  chloroform. 

10.  When  one  part  of  caffeine  is  dissolved  in  hot  water,  and  a 
solution  of  two  parts  of  gallo tannic  acid  added,  the  caffeine  can  be 
accurately  determined  by  precipitating  the  solution  with  lead 
acetate  and  extracting  the  concentrated  filtrate  with  chloroform. 
If  the  liquid  be  concentrated  to  a  syrup,  mixed  with  ignited 
magnesia,  and  dried  at  100°,  the  whole  of  the  alkaloid  cannot  be 
extracted  by  boiling  the  powdered  mass  with  dry  chloroform, 
however  long  the  treatment  be  continued.  If  tannin  prepared  from 
tea  be  substituted  for  gallotannic  acid  in  the  foregoing  experiment, 
a  similar  result  is  obtained. 

11.  When  a  decoction  of  tea  is  substituted  for  the  foregoing 
artificial  mixture  of  caffeine  with  excess  of  tannin  a  precisely 
similar  result  is  obtained.  Whether  sand  or  magnesia  be  used, 
the  alkaloid  is  only  partially  extracted,  even  after  prolonged 
boiling  with  chloroform  or  ether.^     Thus,  decoctions  prepared  by 

^  The  following  experiments  were  made  by  G.  E.  Scott  Smith  in  the 
author's  laboratory.  Fifty  grammes  weight  of  commercial  black  tea  of 
medium  quality  was  powdered  and  boiled  with  water  for  thirty  minutes.  The 
solution  was  filtered  and  made  up  to  1  litre  after  cooling.  Aliquot  parts  of 
the  solution  were  then  treated  in  the  following  manner. 

A.  100  c.c.  (  =  5  grammes  of  tea)  was  evaporated  to  a  syrup  and  mixed  with 
5  grammes  of  ignited  magnesia.  The  mixture  was  dried  thoroughly  at  100°, 
powdered,  and  boiled  with  ether  free  from  alcohol  and  water. 

Caffeine  extracted  by  6  hours'  treatment, 

„  „  4  hours'  further  treatment, . 

II  »  3  hours'      „  „ 

Total,         .      13  0  069 -=1-38  per  cent 

On  subsequently  boiling  the  residue  with  alcohol  an  additional  0'0605  gramme 
of  caffeine  was  extracted,  making  2*59  per  cent,  in  all. 

B.  Was  conducted  like  A,  but  dry  chloroform  was  substituted  for  ether. 
The  total  caffeine  extractable  by  chloroform  was  1'54  per  cent. 

C.  Conducted  like  A,  but  rectified  spirit  was  employed  at  once.  It 
extracted  2*81  per  cent,  of  brownish  caffeine,  which  was  reduced  to  278  per 
cent,  by  re-solution  in  water  and  extraction  with  chloroform. 

D.  Conducted  like  B,  but  sand  was  substituted  for  magnesia.  Treatment 
with  dry  chlorofonn  extracted  successively  0*0365,  0-0175,  0-0135,  and  0-0010 
gramme  of  caffeine  during  nine  hours'  treatment.  On  subsequent  treatment 
with  alcohol  much  tannin  and  colouring  matter  was  extracted.  This  was 
precipitated  by  lead  acetate,  and  tlie  concentrated  filtrate  shaken  with  chloro- 
form. Additional  yield,  O'OTO  gramme,  making  a  total  yield  of  277  per  cent. 
Why  a  portion  of  the  caff"eine  but  not  the  whole  should  be  extracted  by 
chloroform  in  the  absence  of  magnesia  is  not  evident. 

E.  100  c.c.  (  =  5  grammes  tea)  was  heated  to  boiling,  treated  with  solid 


0-059  gramme. 

0-009 

,, 

0-001 

M 

EXTRACTION   OF  CAFFEINE. 


487 


boiling  two  separate  samples  of  black  tea  with  water  were  each 
divided  into  two  equal  parts.  One  of  these  was  precipitated  by- 
lead  acetate,  and  the  caffeine  recovered  from  the  filtered  and  con- 
centrated liquid  by  repeated  agitation  with  chloroform.  The  other 
halves  were  evaporated  to  dryness  with  magnesia  and  the  powdered 
residue  thoroughly  exhausted  by  boiling  with  chloroform,  and 
subsequently  boiled  with  alcohol  for  a  long  time. 


Sample  A. 

30  Minutes' 
Boiling. 

Sample  B. 
20  Minutes'  Boiling. 

Lead  process, 

Magnesia  process :  by  chloroform, 
„             „         by  alcohol,     . 

3-31  per  cent. 
1-18       „ 

2-07  per  cent. 

0-90) 

>  2  06  per  cent. 

lie) 

In  other  experiments  with  mixtures  of  caffeine,  tea-tannin,  and 
excess  of  magnesia,  from  8  to  10  per  cent,  of  the  alkaloid  was  not 
extractable  either  by  chloroform  or  alcohol,  but  could  be  recovered 
by  treatment  with  water. 

12.  When  finely-powdered  tea  is  mixed  with  slaked  lime, 
ignited  magnesia,  or  sand,  made  into  a  paste  with  hot  water,  and 
the  mixture  thoroughly  dried  at  100°,  only  a  fraction  of  the  total 
alkaloid  can  be  extracted  with  chloroform,^  however  carefully  the 
process  be  conducted.  On  subsequently  treating  the  mixture  with 
alcohol,  the  greater  part  of  the  remaining  caffeine  is  ultimately 
dissolved,  but  prolonged  treatment  by  boiling  alcohol  is  necessary 
to  extract  the  caffeine  from  a  mixture  of  tea-extract  or  powdered 
tea  with  magnesia,  and  complete  extraction  is  always  doubtful. 

13.  When  a  decoction  of  tea  is  treated  with  basic  or  neutral 
acetate  of  lead  a  voluminous  precipitate  is  formed.  If  an  aliquot 
part  of  the  liquid  be  filtered,  concentrated,  and  treated  with 
sulphuretted  hydrogen,  sulphurous  acid,  sulphuric  acid,  or  sodium 
phosphate,  to  remove  the  excess  of  lead,  and  again  filtered,  the 
caffeine  may  be  extracted  in  a  condition  of  perfect  whiteness  and 
purity  by  agitation  with  chloroform. 

lead  acetate,  filtered,  and  an  aliquot  part  of  the  filtrate  concentrated,  freed 
from  lead,  and  shaken  repeatedly  with  chloroform.  Caffeine  was  recovered 
equivalent  to  2*63  per  cent,  of  the  tea. 

^  The  remarkable  fact  of  the  retention  of  the  caffeine  of  te*  by  lime  or 
magnesia  in  a  form  incompletely  dissolved  by  cliloroform  was  first  observed  by 
B.  H.  Paul  and  G.  E.  Sco  tt  Smith  (Pharm.  Jour.,  [3],  xxi.  882).  Little 
more  than  one-third  of  the  total  caffeine  was  extractable  by  chloroform  from 
the  lime  mixture,  and  little  more  than  one-half  from  the  magnesia  mixture. 
By  subsequent  treatment  with  alcohol  the  remaining  catieine  was  dissolvsd. 


488  EXTRACTION   OF   CAFFEINE. 

14.  By  prolonged  boiling  with  litharge  a  decoction  of  tea 
becomes  completely  decolorised,  but  the  process  is  tedious.  If 
after  a  time  a  small  addition  of  lead  acetate  be  made,  clarification 
occurs  in  a  few  minutes,  and  an  aliquot  part  of  the  liquid  may  be 
filtered  and  treated  as  in  13. 

From  the  foregoing  statements  (10,  11,  12, 13)  it  is  evident  that 
the  determination  of  caffeine  when  in  a  state  of  solution  presents 
no  great  difficulty,  though  the  widely-used  plan  of  evaporating  the 
liquid  with  sand  and  lime  or  magnesia,  and  extracting  the  dried 
mixture  with  chloroform  or  ether,  gives  gravely  inaccurate  results. 
The  great  difficulty  in  determining  the  total  caifeine  present  in  tea 
is  the  obstinacy  with  which  a  portion  of  the  alkaloid  is  retained  by 
the  vegetable  tissue,  a  fact  which  suggests  that  it  exists  partly  in 
some  insoluble  combination  only  gradually  decomposed  by  boiling 
water  or  alcohol.-^ 

This  form  cannot  be  mere  tannate  of  caffeine,  as  that  compound 
is  moderately  soluble  in  boiling  water.  It  is  more  probable  that 
the  caffeine  itself  is  a  product  of  the  hydrolysis  of  a  more  complex 
body,  possibly  a  glucoside.^  This  conjecture  receives  considerable 
support  from  the  recent  experiments  of  E.  K  n  e  b  e  1  {Apoth.  Zeit.y 
1892,  vii.  112),  who  states  that  the  caffeine  in  the  kola-nut  exists 
as  a  glucoside,  k  o  1  a  n  i  n,  which,  on  boiling  with  water,  or  treat- 
ment with  dilute  acids,  splits  up  into  caffeine,  glucose,  and  kola- 
red.  Ci,Hi3(0H),. 

On  the  supposition  that  the  cellular  structure  of  the  tea  is  the 
cause  of  the  obstinate  retention  of  the  caffeine,  Z  d  1 1  e  r  {Zeitsch. 
Anal.  Ghem.,  xii.  106)  has  i)roposed  to  treat  the  finely-powdered 
tea    with    strong    sulphuric    acid    diluted    with    one-third    of   its 

^  The  following  figures,  obtained  in  the  author's  laboratory,  show  the  rate 
of  exhaustion  on  treating  powdered  black  tea  with  hot  and  cold  water : — 

Caffeine  extracted  by  Boiling  Water. 

la  I  hour 2-46  per  cent. 

In  additional  2  hours,        .      0*72       ,, 
„  4  hours,        .      0-16        „ 

„  6  hours,        .      0-01       „ 

Total  in  12 J  hours,        .      3*35 
*  These  two  figures  have  not  been  transposed. 

Thus  the  extraction  of  the  caffeine  by  boiling  water  was  practically  complete 
after  6  hours'  treatment,  while  with  cold  water  the  total  amount  was  not 
dissolved  after  19  days'  treatment. 

In  both  the  hot  and  cold  water  experiments,  the  infusion  reiluced  Fehling'a 
solution  after  removal  of  the  tannin  by  lead  acetate.  The  caffeine  did  not 
reduce  the  copper  solution  eitlier  before  or  after  boiling  with  dilute  acid. 

2  The  author  has  proved  the  presence  of  a  glucoside  in  some  teas. 


Caffeine  extracted  by  Cold  Water. 

n  3  days,   . 

1*81  per  cent. 

dditional  2  days, 

.      0-29*      „ 

„         2  days,      . 

.      0-70*      „ 

6  days,     . 

.      0-22 

,,          6  days,      . 

.      0-13        „ 

Total  in  19  days,      . 

.      3-15 

DETERMINATION   OF   CAFFEINE.  489 

measure  of  water,  a  ad  heat  the  mixture  at  100°,  till  the  cells  are 
thoroughly  broken  up.  Some  water  is  then  added,  an  excess  of 
hydrated  oxide  of  lead  stirred  in,  and  the  mixture  dried  and 
exhausted  with  alcohol  of  86  per  cent.  The  alcoholic  solution  is 
decolorised  with  animal  charcoal,  and  evaporated  till  caffeine 
crystallises  on  cooling.  From  the  mother-liquor,  the  residual 
caffeine  is  extracted  by  ether.  Zoller  obtained  the  high  proportion 
of  4'92  per  cent,  of  caffeine  from  a  high  quality  of  Himalayan 
tea,  in  addition  to  an  appreciable  quantity  of  theobromine. 

The  author  has  made  a  number  of  experiments  on  the  lines  of 
ZoUer's  process,  modified  in  various  manners,  but,  chiefly  through 
the  remarkable  persistency  with  which  caffeine  is  absorbed  and 
retained  by  the  carbon  formed  by  the  acid  treatment,  they  have 
not  hitherto  resulted  in  the  evolution  of  a  practical  analytical 
method.^ 

^  On  treating  powdered  tea  with  slightly  diluted  sulphuric  acid,  and  heat- 
ing the  mixture  in  the  water-oven  for  an  hour  or  two,  a  black  product  is 
obtained  which  powders  readily.  On  boiling  this  product  with  water,  a 
perfectly  colourless  solution  is  obtained,  from  which,  after  concentration,  per- 
fectly colourless  caffeine  is  extracted  by  agitation  with  chloroform,  either  with 
or  without  previous  removal  of  the  sulphuric  acid  by  boiling  with  litharge  or 
white  lead,  or  neutralisation  with  ammonia.  The  fact  that  a  colourless  liquid 
is  obtained  on  treating  the  charred  tea  with  water  is  due  to  the  absorption  of 
the  colouring  matters  by  the  finely-divided  carbon  formed.  Unfortunately, 
this  product  also  takes  up  a  considerable  proportion  of  the  caffeine,  and  retains 
it  with  such  obstinacy  that  it  is  only  extracted  by  prolonged  and  repeated 
treatments  with  alcohol.  Although  the  entire  amount  present  is  ultimately 
obtainable  in  solution,  the  extraction  is  too  uncertain  and  tedious  to  render 
the  method  a  desirable  one  in  practice.  Exhaustion  direct  with  alcoliol,  ether, 
chloroform,  benzene,  or  water,  either  with  or  without  previous  neutralisation 
of  the  acid  with  litharge  or  magnesia,  equally  failed  to  ensure  ready  extraction. 
Of  the  numerous  experiments  made  in  this  direction  the  following  may  be 
mentioned.  Twenty-five  grammes  of  ordinary  black  tea  of  medium  quality 
was  finely  powdered,  and  treated  with  10  c.c.  of  sulphuric  acid  diluted  with 
one-fifth  of  water.  The  mixture  was  heated  at  100°,  treated  with  a  little  water, 
and  ground  with  excess  of  litharge  till  neutral.  The  mixture  was  redried,  and 
thoroughly  exhausted  successively  in  a  Soxhlet-tube  with  boiling  rectified 
spirit,  boiling  proof-spirit,  and  boiling  water.  The  solutions  were  evaporated, 
and  the  caffeine  extracted  by  repeated  agitation  with  chloroform.  The  follow- 
ing were  the  results  obtained: — 

Yield  of  Caffeine. 

By  strong  alcohol  (sp.  gr.  -838), 3-03  per  cent 

By  subsequent  treatment  with  proof-spirit,  ....       0'50       „ 
By  subsequent  treatment  with  water,   ...  .       0*21       „ 

Total, 3-74 

The  caffeine  isolated  was  snow-white.  These  results  show  that  the  alkaloid 
is  unaltered  by  the  treatment,  and  if  extraction  could  be  effected  with  certainty 


490  DETERMINATION    OF   CAFFEINE. 

As  the  result  of  very  numerous  experiments,  the  author  gives  the 
preference  to  the  following  method  of  extracting  and  determining  the 
cafifeine  in  tea.  It  closely  resembles  a  process  employed  by  S  t  a  h  1- 
schmidt  {Cheni,  Gentralblat,  1861,  396): — Six  grammes  of 
finely-powdered  tea  is  treated  in  a  flask  with  500  c.c.  of  water, 
which  is  then  kept  boiling  under  a  reflux  condenser,  ^o  Soxhlet 
extractor  or  similar  arrangement  is  so  eff'ective  or  rapid  as  actual 
boiling  with  the  water.  Alcohol  effects  no  quicker  or  better  extrac- 
tion than  water,  and  has  the  disadvantage  of  dissolving  chlorophyll. 
After  six  or  eight  hours'  boiling,  the  decoction  may  be  filtered,  the 
residue  washed  on  the  filter,  and  the  filtrate  made  up  with  water  to 
600  C.C.  It  is  then  heated  nearly  to  boiling,  and  about  4  grammes  of 
acetate  of  lead  in  powder  added,  a  reflux  condenser  attached,  and 
the  liquid  boiled  for  ten  minutes.  If  on  removing  the  source  of 
heat  the  precipitate  does  not  curdle  and  settle  readily,  leaving  the 
liquid  colourless,  or  nearly  so,  a  further  addition  of  lead  acetate  must 
be  made  and  the  boiling  repeated.  When  clarification  is  effected, 
the  liquid  is  passed  through  a  dry  filter.  Five  hundred  c.c.  of  the 
filtrate  (  =  5  grammes  of  tea)  is  then  evaporated  to  about  50  c.c, 
when  a  little  sodium  phosphate  is  added  to  precipitate  the  remaining 
lead.  The  liquid  is  filtered,  the  precipitate  washed,  and  the 
filtrate  further  concentrated  to  about  40  c.c,  when  the  caffeine  is 
extracted  by  repeated  agitations  with  chloroform,  at  least  four 
treatments  with  which  are  necessary  to  ensure  the  complete  extrac- 
tion of  the  alkaloid.^  The  separated  chloroform  solutions  are  mixed, 
and  distilled  in  a  tared  flask  immersed  in  boiling  water.  The 
last  traces  of  chloroform  are  removed  while  the  flask  is  still  hot  by  a 
current  of  air,  and  the  residual  alkaloid  is  weighed.  The  caffeine 
thus  isolated  is  snow-white  in  colour,  neutral  in  reaction  to  litmus, 
and  completely  volatile  and  soluble  in  water.  It  does  not  reduce 
Fehling's  solution  either  before  or  after  boiling  with  dilute  acid. 

As  a  precaution,  the  exhausted  tea-powder  should  be  again 
boiled  with  water,  and  the  decoction  treated  as  before.  When 
experience  has  proved  this  to  be  unnecessary,  the  process  can  be 
shortened  by  boiling  the  tea  with  600  c.c  of  water  in  the  first  place, 
and  adding  lead  acetate  without  previously  filtering  from  the 
exhausted  tea.     This  modification  becomes  necessary  in  the  case  of 

by  a  single  solvent,  the  process  would  possess  marked  advnntages.  Substi- 
tution of  magnesia  for  the  oxide  of  lend,  and  various  other  modifications  of  the 
details  equally  failed  to  give  a  satisfactory  result. 

1  In  the  great  majority  of  cases  the  chloroform  separates  readily.  Should 
an  obstinate  emulsion  be  formed,  the  best  plan  is  to  place  the  mixture  in  a 
flask,  distil  off  the  chloroform,  treat  the  residual  liquid  with  a  few  drops  of 
basic  acetate  of  lead,  filter,  and  agitate  the  filtrate  again  with  chloroform. 


PROPORTION   OF   CAFFEINE    IN   TEA. 


491 


certain  teas  {e.g.,    gunpowder),   the    aqueous  decoctions  of  which 
filter  very  slowly. 

The  following  results  by  the  above  process  were  obtained  by 
C.  M.  C  a  i  n  e  s  in  the  author's  laboratory  (Fharm.  Jour.,  [3],  xxiii. 
218).  In  some  instances  the  caifeine  extracted  by  half  an  hour's 
boiling  was  determined,  in  addition  to  the  total  amount  obtained  by 
six  hours'  boiling  with  water.  The  results  refer  to  the  moisture- 
free  teas,  which  were  represe  native  commercial  samples  : — 


Tannin  ;  by 
Lead  Acetate. 

Caffeine. 

Description  of  Tea. 

1 

Extracted  in 
80  minutes. 

Total; 

extracted  in 

6  hours. 

Ceylou,  whole  leaf  (Pelsoe), 

IS'Ol  per  cent. 

3'40  per  cent. 

3-85  per  cent. 

Ceylon,  broken  leaf,   . 

12-31 

... 

4-03 

Assam,  whole  leaf  (Pekoe), 

10-08 

... 

4-02 

Assam,  broken  leaf,    . 

11-33 

... 

4-02        „ 

Java  Pekoe, 

12-93 

... 

3-75        „ 

Kaisow,  red  leaf, 

11-35 

3-41 

Moning,  black  leaf,    . 

11-76 

3-44 

3-74 

Moyune  Gunpowder,  . 

12-95 

2-76 

2-89        „ 

Natal  Pekoe-Souchong,      . 

9-90 

2-71 

3-08 

The  foregoing  process  is  applicable  to  the  determination  of  the 
caffeine  in  coffee^  of  which  12  grammes  may  be  conveniently  em- 
ployed. In  the  presence  of  chicory  the  extracted  alkaloid  is  liable 
to  be  strongly  coloured,  in  which  case  it  should  be  redissolved  in 
water,  a  few  drops  of  caustic  soda  added,  and  the  liquid  again 
exhausted  with  chloroform. 

An  alternative  process  for  the  determination  of  caffeine  in  tea  is 
that  of  P  a  u  1  and  C  o  w  n  1  e  y  (Pharm.  Jour.,  [3],  xviii.  4 1 7),  which 
in  some  respects  resembles  a  method  described  by  Versmann 
{Arch.  Pharm.,  [2],  Ixviii.  148),  and  with  certain  modifications  com- 
municated to  the  author  by  A.  J.  C  o  w  n  1  e  y  is  as  follows  : — Five 
grammes  weight  of  finely-powdered  tea  is  well  mixed  in  a  mortar 
with  2  grammes  of  ignited  magnesia,  the  mixture  thoroughly 
moistened  with  hot  water,  again  triturated,  and  then  dried  at  100°. 
It  is  next  extracted  with  boiling  alcohol,^  and  the  resultant  liquid 
evaporated  nearly  to  dryness.  The  residue  is  boiled  with  50  c.c.  of  • 
water,  and  treated  with  a  few  drops  of  dilute  sulphuric  acid.  When 
cold,  the  liquid  is  filtered  and  repeatedly  shaken  with  chloroform 

^  Experiments  made  in  the  author's  laboratory  showed  that  even  with  the 
most  careful  treatment  it  is  difficult  to  ensure  cmplete  extraction  of  the 
caffeine,  a  small  additional  quantity  being  subsequently  obtained  by  treat- 
ment with  water. 


492  PROPORTION   OF  CAFFEINE   IN   TEA. 

until  exhausted.^  The  united  chloroform  solution  is  then  agitated 
with  a  very  dilute  solution  of  caustic  soda,  which  removes  a  little 
colouring  matter,  so  that  on  subsequently  distilling  off  the  chloro- 
form in  a  weighed  flask,  the  caffeine  is  obtained  jierfectly  pure 
and  colourless,  or  at  most  with  a  faint  green  tinge. 

By  the  foregoing  process,  Paul  and  Cownley  (Pharrn.  Jour., 
[3],  xviii.  417)  found  Indian  and  Cingalese  teas  to  contain  a  much 
larger  percentage  of  caffeine  than,  owing  to  the  faulty  methods  of 
analysis  employed,  is  commonly  supposed.  The  proportion  of 
alkaloid  isolated  from  commercial  samples  of  all  qualities,  and  con- 
taining from  3*6  to  6'8  per  cent,  of  moisture,  ranged  from  322  to 
4:'66  per  cent,  on  tlie  tea  in  its  commercial  condition  (equal  to  3*57 
to  4*99  per  cent,  in  the  moisture-free  tea),  and  bore  no  relation 
to  the  so-called  "  strength  "  of  the  tea.  Java  tea  approached  Ceylon 
tea  in  the  proportion  of  caffeine  present  (294  to  3*78  per  cent.), 
but  China  and  Japan  teas  were  generally  poorer  in  alkaloid,  the 
proportion  in  these  products  ranging  (for  a  limited  number  of 
samples)  from  2*20  to  3"46  per  cent.  J.  H.  Small  obtained,  by 
Paul  and  Cownley's  method  of  assay,  from  1*79  to  2 "30  per  cent, 
of  caffeine  from  Japanese  teas,  and  from  2*38  to  3 "54  per  cent, 
from  Chinese  and  Indian  teas. 

Paul  and  Cownley  have  also  .employed  the  foregoing  method 
of  determining  caffeine  for  the  assay  of  coffee  (Pharm.  Jour.,  [3], 
xvii.  565,  648).  The  caffeine  obtained  by  evaporation  of  the 
chloroform  is  liable  to  contain  a  small  quantity  of  a  brownish 
waxy  or  resinous  impurity,  and  hence  should  be  purified  by 
re-solution  in  boiling  water,  and  recovered  by  evaporating  the 
filtered  solution  and  drying  the  residual  alkaloid  at  100°.  By  this 
process  they  found  the  proportion  of  caffeine  in  coffee-berries  to 
vary  within  comparatively  narrow  limits,  and  not  to  be  materially 
affected  by  roasting.  Hence  they  recommend  the  determination 
of  the  alkaloid  in  commercial  coffee  as  a  means  of  estimating  the 
proportion  of  chicory  or  other  admixture  present. 

Theobromine.     Dimethyl-xanthine. 

CyHgN.O^;  or,  C,-K,{CR,\-^fi,. 

The  constitution  and  synthesis  of  theobromine  have  already  been 
described  (page  473).  It  is  the  lower  homologue  of  caffeine,  to 
which  alkaloid  it  presents  a  close  general  resemblance,  but  differs 
considerably  from  it  in  its  solubilities. 

1  In  Paul  and  Covvnley's  experience,  six  or  seven  successive  treatments  with 
chloroform  (using  from  30  to  40  c.c.  each  time)  are  necessary  to  effect  the 
complete  extraction  of  the  caffeine  from  the  solution  yielded  by  5  grammes  of  tea. 


CHARACTERS  OF  THEOBROMINE.  493 

Theobromine  is  isomeric  with  theophylline  and  paraxanthine. 

Theobromine  exists  naturally  in  cocoa,  the  seed  or  bean  of 
Theohroma  cacao ;  and  together  with  caffeine  in  the  kola  nut 
(StercuUa  acuminata).  An  alkaloid  apparently  identical  with  theo- 
bromine was  found  by  ZoUer  in  a  specimen  of  Himalayan  tea. 

Theobromine  forms  a  white,  crystalline  powder,  which  under  the 
microscope  appears  as  trimetric  needles  and  club-shaped  groups. 
When  heated  to  about  290°  it  sublimes  without  decomposition  or 
previous  fusion. 

Theobromine  has  a  very  bitter  taste,  which  is  only  slowly 
developed.  Its  physiological  action  is  shnilar  to  that  of  caffeine, 
but  more  powerful.  In  large  doses  it  produces  well-defined 
poisonous  effects.  It  is  eliminated  by  the  kidneys,  and  can  be 
detected  in  the  urine. 

Theobromine  dissolves  in  1600  parts  of  ice-cold  or  148  of  boil- 
ing water.  In  cold  alcohol  also  it  is  only  very  slightly  soluble 
(1  in  4280),  and  requires  fully  400  parts  at  the  boiling-point,  but 
dissolves  far  more  easily  in  80  per  cent,  spirit.  It  requires  1700 
parts  of  cold  or  600  of  boiling  ether  for  solution,  dissolves  in  105 
parts  of  boiling  chloroform,  is  soluble  in  amylic  alcohol,  dissolves 
slightly  in  benzene,  and  is  insoluble  in  petroleum  spirit. 

Theobromine  dissolves  in  acids,  and  is  precipitated  from  the 
solution  by  alkalies,  but  is  soluble  in  excess  of  ammonia  or  fixed 
alkalies.  It  is  wholly  extracted  from  its  solution  in  caustic  soda 
by  agitation  with  chloroform. 

Theobromine  is  a  weak  base,  its  salts  being  readily  decomposed 
by  water  with  separation  of  the  alkaloid  (compare  Caffeine,  page  482). 
The  liydrochloride,  BHCl-j-HgO,  and  nitrate,  BHNOg,  lose  all 
their  acid  at  100°.  B2H2PtCl6+2H20  crystallises  in  oblique 
prisms,  which  effloresce  in  the  air  and  become  anhydrous  at  100°. 
BHAuCl^  forms  tufts  of  yellow  needles. 

An  aqueous  solution  of  theobromine  forms  with  mercuric  chloride 
a  white  crystalline  precipitate,  sparingly  soluble  in  water  and  alcohol. 

One  of  the  most  definite  and  insoluble  compounds  of  theobro- 
mine is  that  with  nitrate  of  silver.  When  a  very  dilute  aqueous 
solution  of  theobromine  nitrate  is  treated  with  silver  nitrate, 
silver-white  needles  containing  CyHgN^Og, AgN O3  form  after  a 
short  time.  The  compound  is  only  sparingly  soluble  in  water,  and 
may  be  dried  without  change  at  100°.  If  a  solution  of  theobro- 
mine in  ammonia  be  treated  with  nitrate  of  silver,  a  gelatinous 
precipitate  is  obtained  which  dissolves  easily  in  warm  ammonia, 
and  on  boiling  the  solution  for  some  time  hydrated  silver 
theobromine,  CyH^AgN^Og,  separates  as  a  granular  nearly 
insoluble  precipitate. 


494  REACTIONS   OF   THEOBROMINE. 

Theobromine  reacts  with  alkalies  like  a  weak  acid  and  forms 
definite  salts.  Thus  the  sodium  salt  is  obtained  by  adding  theo- 
bromine to  soda-lye  until  a  portion  remains  undissolved  after  long 
standing,  and  evaporating  the  filtrate  under  the  air-pump.  The 
product  is  destitute  of  crystalline  structure,  is  extremely  soluble  in 
water,  has  a  strong  alkaline  reaction,  and  absorbs  carbon  dioxide 
from  the  air.  The  barium  salt,  {C^^.j^ fi^^d^,  separates  on 
adding  theobromine  to  baryta-water  as  a  mass  of  microscopic 
needles,  and  is  obtainable  as  a  snow-white  felt  of  silky  needles  by 
slowly  cooling  its  solution  in  hot  water.  If  the  solution  be  rapidly 
cooled,  it  solidifies  to  a  stiff  jelly. 

Theobromine  yields  no  product  similar  to  caffeidine  when  boiled 
with  concentrated  baryta-water  or  caustic  alkalies.  By  such  treat- 
ment, as  also  when  heated  with  hydrochloric  acid  under  pressure  to 
240°,  theobromine  gives  the  same  products  as  caffeine  (page  478). 

The  best  precipitant  of  theobromine  is  a  solution  of  sodium 
phosphotungstate  (page  136),  which  should  be  added  to  a  solu- 
tion strongly  acidulated  with  sulphuric  or  nitric  acid.  The  yellow 
precipitate  sliould  be  mixed  with  sodium  carbonate  or  magnesia, 
dried,  and  the  mixture  exhausted  with  chloroform,  which  dissolves 
the  theobromine. 

When  theobromine  is  heated  with  dilute  sulphuric  acid  and 
lead  dioxide,  carbon  dioxide  is  evolved.  When  once  started,  the 
reaction  continues  without  further  application  of  heat,  and  if  excess 
of  the  oxidising  agent  and  too  long  heating  be  avoided  the  filtered 
liquid  is  colourless,  but  evolves  ammonia  on  treatment  with  a 
caustic  alkali,  separates  sulphur  from  sulphuretted  hydrogen,  colours 
the  skin  purple-red,  and  immediately  turns  blue  when  treated  with 
a  moderate  quantity  of  magnesia.  Excess  of  magnesia  destroys  the 
colour,  which  may  be  restored  by  cautious  addition  of  sulphuric  acid. 

By  oxidation  with  chromic  acid  mixture,  theobromine  yields 
carbon  dioxide,  methylamine,  and  methyl-parabanic  acid, 
C3H(CH3)N203.-^  Aqueous  chlorine  converts  it  into  methyl- 
urea,  CH3(CH3)N20,  and  m  e  t  h  y  1  -  a  1 1 0  X  a  n,  G^{CR^l^jd^ ; 
while  treatment  with  hydrochloric  acid  and  potassium  chlorate 
oxidises  it  to  di  m  ethyl- alloxan  tin,  C8H4(CH3)2]S'408. 
Theobromine  gives  with  oxidising  agents  and  ammonia  the  same 
colour-reactions  which  characterise  caffeine  (page  480). 

Isolation  and  Determination  of  Theobromine. 

Theobromine  may  be  isolated  by  much  the  same  methods  as  those 

^  Methyl-parabanic  acid  is  easil)'  soluble  in  hot  water,  from  which 
it  crystallises  in  transparent  prisms,  melting  at  148°.  Warmed  with  ammonia 
and  calcium  chloride,  it  gives  a  precipitate  of  calcium  oxalate  (compare  Choles- 
trophane,  page  481). 


ISOLATION    OF   THEOBROMINE.  495 

used  for  the  determination  of  caffeine,  having  regard  to  the  far  less 
ready  solubility  of  the  former  alkaloid  in  water,  alcohol,  and  other 
solvents.  As  in  the  case  of  caffeine,  the  methods  used  by  observers 
who  have  recorded  high  yields  of  theobromine  are  more  trust- 
worthy than  those  of  chemists  who  have  succeeded  in  isolating 
comparatively  small  proportions. 

For  the  preparation  of  theobromine,  E.  Schmidt  (Archiv  der 
Pharmacie,  ccxxi.  656)  mixes  commercial  cocoa  (freed  as  far  as 
possible  from  fat  by  pressure)  with  half  its  weight  of  freshly- 
slaked  lime,  and  extracts  the  mixture  with  boiling  alcohol  of  80 
per  cent,  (by  volume).  On  cooling  the  alcoholic  extract,  theo- 
bromine separates  out,  and  on  recrystallisation  from  hot  alcohol  is 
obtained  as  a  white,  crystalline  anhydrous  product. 

Before  extracting  theobromine  it  is  preferable  to  get  rid  of  the 
fat  by  exhausting  the  finely-divided  cocoa  with  petroleum  spirit. 
The  residue  is  made  into  a  paste  with  water  and  ignited  magnesia, 
dried  at  100°,  and  exhausted  with  spirit  of  80  per  cent. 

Another  method  of  extracting  the  theobromine  from  cocoa  is  to 
exhaust  the  substance  with  water  or  dilute  alcohol,  precipitate  the 
solution  with  acetate  of  lead,^  separate  the  lead  from  the  filtered 
solution  by  sulphuretted  hydrogen,  evaporate  the  filtrate  to  dryness, 
and  extract  the  theobromine  from  the  residue  by  boiling  chloroform. 

Caffeine  may  be  separated  from  theobromine  by  treating  the 
mixed  alkaloids  with  cold  benzene,  in  Avhich  theobromine  is 
practically  insoluble. 

James  Bell  {Foods,  i.  85)  boils  100  grains  of  the  cocoa 
repeatedly  with  benzol,  which  dissolves  fatty  matters  and  caffeine.^ 
The  residue  is  mixed  in  a  mortar  with  100  grains  each  of  sand 
and  calcined  magnesia  and  sufficient  water  to  form  a  paste,  the 
product  dried  at  100"",  and  repeatedly  boiled  with  strong  alcohol. 
The  solution  is  filtered,  distilled,  and  the  residual  theobromine 
dried  at  100°  and  weighed.  It  is  freed  from  traces  of  fat  and 
caffeine  by  treatment  with  hot  benzene,  and  then  treated  twice  with 

^  By  using  a  known  volume  of  liquid  and  filtering  off  four-fifths  or  other 
known  proportion,  the  tedious  washing  of  the  bulky  lead  precipitate  may  be 
avoided.  When  once  the  alkaloid  is  in  solution,  the  method  recommended  by 
the  author  for  the  determination  of  caffeine  (page  490)  is  also  applicable  to 
theobromine.     The  chloroform  should  be  used  warm. 

2  Bell  refers  to  this  product,  which  was  especially  yielded  by  Trinidad  cocoa, 
as  a  "theine-like  alkaloid;"  but  as  Weigmann  and  E.  Schmidt  have 
both  proved  the  occurrence  of  caffeine  in  cocoa  {Annalen,  ccxvii.  306)  there  seems 
no  doubt  as  to  the  nature  of  the  substance  observed  by  Bell.  He  separated 
it  from  the  fatty  matter  by  boiUng  with  water.  The  aqueous  liquid  was 
evaporated,  and  the  alkaloid  purified  by  successive  solution  in  water  and 
benzene. 


496 


DETERMINATION   OF   THEOBROMINE. 


a  little  ice-cold  water.  It  is  thus  obtained  white  and  perfectly  pure, 
except  for  the  presence  of  a  trace  of  mineral  matter.^  Bell  found 
by  this  process  the  following  proportions  of  alkaloid  in  cocoa : — 


Cocoa. 

Theobromine. 

Theine-lilce  Alkaloid 
(Caffeine). 

Guayaquil  (nibs), 
Grenada  (nibs), 
Surinam  (nibs), 
Trinidad  (nibs),      . 
Trinidad  (huslcs),   . 

0-54  per  cent. 
0-91        „ 
0-78        „ 
0-59       „ 
102        „ 

Trace. 

Trace. 

0  02  per  cent. 

0-25 

0-33        „ 

It  is  probable  that  Bell's  results  are  considerably  below  the 
truth,  since  Pay  en  found  2  per  cent.;  Mi  tscherlich,  15 
per  cent.;  Trojanowski,  1-2  to  4'6  per  cent.;  while  G. 
Wolfram  found,  in  six  samples  of  dried  cocoa-beans  divested  of 
their  shells,  from  1*34:  to  1*66  per  cent,  of  theobromine,  with  an 
average  of  1*56  per  cent.  The  dried  husks  of  the  same  beans 
contained  from  0"42  to  1*11  per  cent,  of  theobromine,  with  an 
average  of  0*76  per  cent.  "Weigmann  found  0*17  per  cent,  of 
caffeine  in  the  kernel  and  from  O'll  to  0*13  per  cent,  in  the  shell 
of  cocoa-beans. 

G.  Wolfram  {Dingl.  Polyt.  Joiir.^  ccxxx.  240)  has  described 
the  following  method  of  determining  theobromine.^  If  shelled 
cocoa-beans  are  to  be  analysed,  they  are  ground  up  in  a  hot  mortar 
to  a  thick  paste.  Ten  grammes  of  this  mass  or  30  grammes  weight 
of  chocolate  is  digested  for  some  time  in  hot  water,  and  the  solution 
filtered.  The  filtrate  is  precipitated  with  ammoniacal  acetate  of 
lead,  the  solution  filtered  hot,  and  the  precipitate  washed  with 
boiling  water  till  the  washings  (acidulated  with  nitric  acid)  cease 
to  give  a  yellow  precipitate  with  Scheibler's  reagent  (page  136). 
The  filtrate  is  rendered  slightly  alkaline  with  soda,  concentrated  to 
about  50  c.c,  strongly  acidulated  with  sulphuric  acid,  and  the  lead 
sulphate  separated  by  filtration.     The  filtrate  is  now  treated  with 

1  This  might  readily  be  removed  by  dissolving  the  alkaloid  in  hot  chloro- 
form, and  such  treatment  would  obviate  the  necessity  of  treating  the  impure 
alkaloid  with  water,  wbich  cannot  be  performed  without  loss.  Bell's  process 
is  nearly  identical  with  that  previously  described  by  T  r  o  j  a  n  o  w  s  k  y  {Arch. 
Pharm.,  [3],  x.  32  ;  Jour.  Chem.  Soc,  xxxii.  363),  except  for  the  substitution 
of  "benzol"  for  petroleum  ether,  a  change  which  suggests  confusion  between 
the  two  solvents,  and  probably  causes  loss  of  theobromine. 

2  A  similar  method  has  been  successfully  employed  by  Mitscherlich 
for  the  isolation  of  theobromine  from  urine. 


DIURETIN.  497 

a  large  excess  of  sodium  phosphotungstate  (Scheibler's  reagent). 
The  coagulation  of  the  slimy,  yellowish-white  precipitate  of  theo- 
bromine phosphotungstate  is  facilitated  by  warming  and  stirring 
the  mixture  gently.  After  standing  several  hours,  the  precipitate 
is  filtered  off  and  washed  with  dilute  sulphuric  acid  (6  to  8  per 
cent.  H2SO4).  Wolfram  then  decomposes  the  precipitate  by  hot 
baryta-water,  precipitates  the  filtrate  with  sulphuric  acid,  removes 
the  excess  of  the  latter  by  barium  carbonate,  evaporates  the  filtered 
liquid,  and  weighs  the  residual  theobromine,  which  is  then  ignited 
and  any  ash  deducted.  L.  L  e  g  1  e  r  (Zeitschr.  Anal.  Chem.y  xxiii. 
89)  dissolves  the  precipitate  in  caustic  soda  free  from  chlorides, 
nearly  neutralises  with  sulphuric  acid,  evaporates  to  dryness  with 
sand,  and  extracts  the  residue  with  amylic  alcohol.  The  solution 
is  evaporated  to  dryness  at  100°,  the  residue  weighed,  and  the  loss 
of  weight  on  ignition  regarded  as  theobromine.  A  preferable  plan 
to  either  would  be  to  mix  the  moist  theobromine  phosphotung- 
state with  sodium  carbonate,  dry,  and  extract  with  boiling 
chloroform,  which  on  evaporation  would  leave  the  theobromine 
in  a  pure  state. 

DiURETiN.  Under  this  name  a  preparation  has  been  intro- 
duced into  medicine  having  the  constitution  of  a  combination 
of  sodium-theobromine  and  sodium  salicylate,  and  the  formula 
C7H7XaN40,,C6H/OH).COONa. 

Diuretin  is  colourless,  odourless,  slightly  soluble  in  cold  water, 
and  insoluble  in  chloroform  or  ether,  but  readily  soluble  in  hot 
water  or  warm  dilute  alcohol.  The  physiological  action  of  diuretin 
is  said  to  be  quite  distinct  from  that  of  the  analogous  com- 
pound of  caffeine.  It  is  stated  to  be  much  more  readily  absorbed 
than  simple  theobromine,  and  to  be  devoid  of  any  toxic  properties, 
or  of  the  peculiar  excitant  influence  on  the  central  nervous  system 
exerted  by  caffeine. 

Owing  to  the  high  price  of  theobromine  as  compared  with  caffeine, 
substitution  of  the  former  by  the  latter  alkaloid  is  possible,  and 
hence  G.  Vulpius  {Jour.  Cliem.  Soc.^  Iviii.  1475)  has  pro- 
posed the  following  method  for  the  assay  of  diuretin : — 2  grammes 
weight  of  the  sample  is  dissolved  in  10  c.c.  of  water  in  a  porcelain 
dish,  the  aolution  acidulated  with  hydrochloric  acid,  and  then 
rendered  faintly  alkaline  with  ammonia.  The  liquid  is  kept  for 
three  hours  at  the  ordinary  temperature,  and  frequently  stirred. 
The  separated  theobromine  is  then  collected  on  a  tared  filter,  the 
filtrate  being  used  to  transfer  the  last  portions  from  the  dish. 
Gentle  suction  is  used  to  remove  the  last  of  the  mother-liquor, 
and  the  theobromine  is  th-en  washed  twice  with  10  c.c.  of  cold 
water,   dried   at    lOO"*,  and  weighed.       By   this  method,  Vulpius 

VOL.  III.  PART  II.  ^  I 


498  THEOPHYLLINE. 

recovered  from  41  to  41 J  per  cent,  of  theobromine  from  pure 
diuretin,  6  J  per  cent,  remaining  in  the  filtrate  and  washings. 
Making  this  allowance,  the  theobromine  should  not  be  less  than 
46  J  per  cent.,  and  that  isolated  should  melt  when  carefully  heated, 
be  completely  volatile,  and  dissolve  readily  in  caustic  soda  solution. 
From  the  filtrate  from  the  theobromine,  the  salicylic  acid  can  be 
isolated  by  acidulating  with  hydrochloric  acid  and  agitating  with 
chloroform.  The  separated  chloroform  is  washed  with  water  to 
remove  mineral  acid,  a  little  water  and  a  drop  of  phenolphthalein 
solution  added,  and  the  liquid  then  titrated  with  decinormal  caustic 
alkali.  Each  c.c.  of  -§-  alkali  required  for  neutralisation  represents 
0'0138  gramme  of  salicylic  acid.  Diuretin  should  contain  38 J  per 
cent,  of  salicylic  acid.  The  titration  completed,  the  chloroform  may 
be  separated  and  evaporated,  when  the  residue  will  represent  the  6 "5 
per  cent,  of  theobromine  not  previously  separated,  together  with 
any  caffeine  the  preparation  may  have  contained.  To  prove  the 
absence  of  cafi'eine  in  diuretin,  Yulpius  recommends  that  1  gramme 
of  the  sample  should  be  dissolved  in  5  c.c.  of  water,  and  the  solu- 
tion neutralised  with  hydrochloric  acid,  when  the  theobromine 
will  form  a  milky  precipitate  readily  soluble  in  soda  solution.  If 
the  mixture  be  shaken  with  its  own  measure  of  chloroform,  not 
more  than  0*005  gramme  of  residue  should  remain  on  evaporating 
the  separated  chloroform. 

Theophylline,  C^HglSr^Og,  a  base  existing  in  minute  quantity 
in  tea,  is  isomeric  with  theobromine  and  paraxanthine 
(occurring  in  human  urine).  According  to  A.  Kossel^  {Berichte, 
xxi.  2164;  Pharm.  Jour.,  [3],  xix.  41;  Jour.  Cliem.  Soc.j  liv. 
1115),  theophylline  crystallises  with  1  aqua,  which  it  loses  at  110°. 
It  melts  at  264°.  It  is  easily  soluble  in  warm  water,  but  spar- 
ingly in  cold  alcohol,  and  is  extremely  soluble  in  very  dilute 
ammonia.      It  forms  a   crystalline   hydrochloride,   nitrate,   chloro- 

^  For  its  isolation,  Kossel  extracts  tea- leaves  with  alcohol  and  evaporates 
the  tincture  to  a  syrup,  when  most  of  the  cafleine  crystallises  out  on  cooling. 
The  filtrate  is  diluted  with  water,  acidulated  with  sulphuric  acid,  filtered  after 
a  considerable  time,  made  alkaline  with  ammonia,  and  precipitated  with 
nitrate  of  silver.  After  standiiij^  twenty-four  hours  the  precipitate  is  filtered 
off  and  warmed  with  nitric  acid  ;  on  cooling  the  liquid,  the  silver  nitrate 
compounds  of  adenine  and  hypoxanthiiu  (sarcine)  crystallise  out.  The  acid 
filtrate  is  treated  with  ammonia,  and  the  precipitate  suspended  in  water 
acidulated  with  nitric  acid  and  decomposed  by  sulphuretted  hydrogen.  On 
concentrating  the  filtrate,  xantJdne  first  crystallises,  and  subsequently  theo- 
phylline. The  mother-liquor  is  precipitated  with  mercuric  nitrate,  the  free 
acid  being  nearly  neutralised  with  soda.  The  precipitate  is  then  separated, 
suspended  in  water,  and  decomposed  by  sulphuretted  hydrogen,  and  tht 
theophylline  recovered  from  the  filtrate. 


MANUFACTURE   OF  TEA.  499 

platinate,  auro-chloride,  and  mercuro-chloride,  and  combines  with 
soda  to  form  a  readily  soluble  compound.  When  evaporated  with 
chlorine-water,  theophylline  yields  a  scarlet  residue,  changed  to 
violet  on  addition  of  ammonia.  The  silver-derivative,  CyHyAgN^Og, 
is  obtained  as  an  amorphous  precipitate  on  adding  silver  nitrate 
to  an  aqueous  solution  of  theophylline.  It  crystallises  from  hot 
ammonia,  and  dissolves  readily  in  nitric  acid.  The  methyl- 
derivative,  CyHyMeN^Og,  prepared  by  heating  the  last  sub- 
stance with  methyl  iodide  and  methyl  alcohol,  melts  at  229**,  and 
is  identical  with  caffeine. 

Tea.^ 

The  tea  of  commerce  is  the  prepared  leaf  of  Thea  sinensis  (and 
perhaps  allied  species),  a  shrub-like  plant  belonging  to  the  genus 
Camellia.  It  occurs  native  in  the  Himalayas  and  Assam,  has  long 
been  cultivated  in  China  and  Japan,  and  is  now  raised  largely  in 
British  India,  Ceylon,  Brazil,  &c.2 

It  was  formerly  believed  that  green  and  black  teas  were  the 
product  of  distinct  plants,  but  it  is  now  known  that  the  difference 
is  due  to  the  method  of  preparation ;  black  tea  having  undergone 
a  certain  amount  of  fermentation,  whereas  in  green  tea  this  change 
is  carefully  prevented.^  The  leaves  are  gathered  from  the  plants 
four  times  a  year,  and  are  distinguished  according  to  their  age. 
Each  leaf  is  at  first  a  "  flowery  Pekoe "  leaf,  which  is  the  name 
applied  to   the   leaf-bud.      This  becomes   in   succession   "orange 

^  French  ;  le  Thi.     German ;  der  Thee. 

2  The  Report  of  H.  M.  Customs  for  1891  to  1892  states  that  the  weight  of  tea 
imported  from  the  peninsula  of  Hindostan  showed  a  decrease  of  three  million 
pounds,  while  that  from  Ceylon  increased  by  more  than  sixteen  millions  of 
pounds,  exceeding  for  the  first  time  that  of  China  tea,  which  now  forms  only 
one-fourth  of  our  entire  consumption, 

*  "  For  black  teas,  the  leaves  are  withered  a  little,  rolled  to  Hberate  the  juices, 
left  in  balls  for  the  proper  state  of  fermentation,  then  sun-dried  and  subjected 
to  a  careful  firing  in  a  furnace.  For  green  teas,  the  fresh  leaves  are  first  withered 
in  hot  pans,  then  rolled  to  free  the  juices,  slightly  roasted  in  the  pans,  sweated 
in  bags,  and  returned  to  the  pans  for  a  final  slow  roasting,  with  stirring,  for 
eight  or  nine  liours,  beginning  at  the  temperature  of  160°  F.,  and  falling  to 
120°  F.  at  the  close  "  ( A.  B.  P  r  e  s  c  o  1 1 ).  The  methods  of  preparing  tea  vary 
materially  in  different  countries.  In  India,  the  manufacturing  processes  are 
veiy  much  simplified,  being  reduced  to  five,  instead  of  the  twelve  practised  in 
China,  In  addition,  the  work  is  nearly  all  accomplished  by  machinery,  so 
that  the  leaves  are  not  touched  by  the  labourers,  except  in  picking.  This  is 
partially  true  also  of  Japanese  tea,  whereas  Chinese  tea  is  manipulated  almost 
entirely  by  hand,  except  when  the  feet  are  employed.  A  detailed  description 
of  the  method  of  preparing  Japanese  tea  has  been  given  by  J.  Takyama 
{Chem.  News,  1.  299). 


500  VARIETIES   OF   TEA. 

Pekoe,"  "Pekoe,"  "Souchong  1st,"  " Souchong  2nd,"  "Congou," 
and  finally  "  Bohea."^  In  some  cases  the  leaves  are  classified  simply 
as  Pekoe,  Souchong,  and  Bohea.  The  first  and  second  pickings  of 
the  season  furnish  the  finest  teas ;  but  the  quality  of  the  product 
depends  on  the  age  of  the  tree  as  well  as  the  age  of  the  leaf ;  the 
finest  teas  being  produced  from  the  young  leaves  of  young  plants, 
whilst  old  leaves,  and  the  leaves  of  old  wood,  are  deficient  both  in 
flavour  and  extract.^ 

Besides  the  foregoing  distinctions,  based  on  the  age  of  the  leaf, 
there  are  other  classifications  based  on  the  district  of  growth  and 
the  method  of  preparation.  Thus  among  the  chief  commercial 
varieties  of  hlaclc  tea  are  Assam,  Ceylon,  Japan,  Kaisow,  Moning, 
and  Oolong ;  and  those  of  green  tea,  Gunpowder,  Hyson,  Young 
Hyson,  Imperial,  and  Twankay.  Green  tea  has  much  declined  in 
popularity  of  late  years.  "  Caper  tea  "  is  always  more  or  less  of  a 
factitious  character. 

Very  few  trustworthy  complete  analyses  of  tea  have  been  pub- 
lished ;  and,  indeed,  they  have  but  a  limited  interest  or  practical 
value,  since  the  tea  is  not  consumed  as  a  whole,  but  invariably 
infused,  and  the  infusion  contains  the  tea-constituents  in  very 
difi'erent  proportions  from  those  in  which  they  exist  in  the  leaf. 

An  average  of  sixteen  analyses  of  tea  made  by  K  o  n  i  g 
showed: — Moisture,   11*49  per  cent.;  caffeine,  1'35  ;  albuminous 

^  Pe^-Ao  signifies  "white  hairs  ;"  Sou-chong,  "  little  plant ;"  and  Con-gou, 
"labour." 

2  0.  Kellner  {Land.  Fersuchs-Stat. ,  1886,  370;  Jour.  Ghem.  Soc,  Hi.  73) 
has  published  analyses  of  the  leaves  of  the  same  tea-plant  during  six  months 
(May  to  November).  His  figures  show  a  decrease  in  the  proportion  of  total 
nitrogen,  and  almost  entire  disappearance  of  amido- nitrogen  in  the  older 
leaves.  The  cafieine  fell  from  2-85  to  I'OO  (estimated  by  evaporating  the 
infusion  to  dryness  with  magnesia,  and  extracting  with  ether),  and  the  tannin 
rose  from  8*53  to  12 IG.  The  hot- water  extract  remained  practically  stationary, 
while  the  ether-extract  rose  from  6*48  to  22*19.  The  ash  increased  from  4  69 
to  5'04  only,  but  in  July  fell  to  4*29,  and  in  September  reached  5*11.  All  the 
ash  determinations  are  improbably  low,  and  suggest  ignition  at  too  high  a 
temperature.  Such  an  error  would  vitiate  the  potash  determinations,  which 
showed  a  variation  from  49 "06  in  May  to  17 '31  in  November.  The  manganese 
(MugOJ  ranged  from  1*21  to  2*48,  and  the  chlorine  from  1'04  to  1".56  per  cent. 
of  the  ash. 

The  albuminoids  were  determined  by  a  modification  of  Stutzer's  process. 
The  aqueous  decoction  of  2  grammes  in  100  c.c.  of  water  was  treated  with 
20  c.c.  of  a  10  percent,  solution  of  cupric  sulphate,  and  a  titrated  solution  of 
caustic  soda  in  such  quantity  as  to  leave  a  little  copper  in  solution.  The 
liquid  filtered  rapidly,  and  was  free  from  albuminoids.  The  precipitate  was 
washed  first  with  hot  water  and  then  vrith  strong  alcohol.  The  contained 
nitrogen  was  determined  by  ignition  with  soda-lime. 


COMPOSITION   OF  TEA. 


601 


matters,  22*22;  ethereal  oil, ^  067;  gum  and  dextrin,  7*13; 
tannin,  12'36;  fat,  wax,  and  chlorophyll,  3*62;  other  nitrogen- 
free  matters,  16'75  ;  woody  fibre,  20'30 ;  and  ash,  5'11  per  cent. 

J.  M.  Eder  {Dingl.  Polyt  Jour.^  ccxxxi.  445,  526)  gives  the 
following  as  the  average  composition  of  tea.^ 


^1.  Soluble  in  water—  Per  cent. 

Moisture, 10  0 

Tannin, 100 

Gallic  acid,  oxalic  acid,  and 

quercetin, 
Boheic  acid,       .        .        .        , 
Caffeine  or  theine,    . 
Tea  oil,       .... 
Albuminous  bodies  (probably  ) 

legumin),        .       .        .         j 
Gummy  substances,  dextrin, 

and  sugar. 
Mineral  matters,       .       .        ,1-7 


0-2 

01 
2-0 
0-6 

120 
3  to  4 


B.  Insoluble  in  water — 
Chlorophyll,   . 
Wax,       .       .       .       .        , 

Resin 

Colouring  matter,  . 
Extractive   matter,    mostly 

soluble  in  nitric  acid, 
Cellulose,       .       .       .       , 
Albuminous  bodies. 
Mineral  matters,   . 


Per  cent. 
1-8  to  2-2 
.      0-2 
.      3-0 
.      1-8 


16-0 

20-0 
12-7 

4*0 


^  Essential  Oil  is  determined  by  distilling  a  considerable  quantity  of  tea 
(200  grammes)  with  1500  c.c.  of  water,  and  agitating  the  distillate  with  ether. 
On  distilling  off  the  ether  the  tea  oil  remains.  Eder  found  0*52  per  cent,  of 
oil  in  gunpowder  and  0'41  per  cent,  in  pekoe  bloom  tea  by  this  process. 
Batters  hall  employs  10  grammes  of  tea.  and  saturates  the  distillate 
with  calcium  chloride  before  agitating  with  ether.  A  good  sample  of  black 
tea  yielded  0'87  per  cent,  of  volatile  oil  when  examined  by  this  method. 

Tea  oil  is  a  bright  yellow  liquid,  which  darkens  and  resinifies  on  exposure  to 
the  air  for  a  few  days,  and  turns  reddish  brown  with  nitric  acid.  Even  on 
exposing  the  aqueous  distillate  from  tea  to  the  air  for  some  time,  it  loses  its 
aromatic  odour,  and  little  or  no  oil  can  then  be  separated  from  it  by  ether, 
and  even  if  the  distillate  be  kept  iu  closed  vessels  the  aroma  is  soon  lost. 
These  facts  explain  the  fact  that  tea  leaves  lose  their  bouquet  by  age  or 
exposure. 

Q u e r c i t r i n  and  Q u e r c i t i n,  stated  byHlasiwetz  to  be  present  in 
tea,  are  described  in  Vol.  III.  Part  I.  page  341. 

Boheic  Acid,  CyHjoOg,  according  to  Rochleder  {Annalen,  Ixiii.  202), 
exists  to  the  extent  of  0*1  to  0*2  per  cent,  in  black  tea.  It  is  prepared  by 
precipitating  a  boiling  infusion  of  tea  with  acetate  of  lead,  neutralising  the 
filtered  liquid  with  ammonia,  suspending  the  washed  precipitate  in  absolute 
alcohol,  and  decomposing  it  by  sulphuretted  hydrogen.  The  filtrate  is 
evaporated  to  diyness  m  vacuo,  and  the  residual  l)oheic  acid  purified  by 
resolution  iu  water,  &c.  It  is  a  yellow  resinous  body,  melting  at  100°  to  a 
tenacious  manner,  and  decomposed  on  exposure  to  air.  It  is  extremely  soluble 
in  water  and  a^.cohol,  and  giving  a  brown  coloration  but  no  precipitate  with 
ferric  chloride.     The  salts  are  mostly  insoluble  and  amorphous. 

^  Eder's  figures  for  mineral  matters  soluble  in  water  are  considerably  lower 
than  any  other  observer,  and  his  proportion  of  insoluble  matters  is  in  excess 
and  of  soluble  in  deficiency  of  those  usually  recorded.     His  tannin,  which  was 


502 


JAPANESE  TEA. 


The  following  analyses  by  Y.  K  o  z  a  i  {Bulletin,  No.  7,  Imperial 
College  of  Agriculture,  Japan)  have  a  special  value  owing  to  the 
author's  knowledge  of  tea  manufacture.  Special  precautions  were 
taken  in  sampling  the  leaves  to  ensure  strictly  parallel  specimens 
being  taken.  The  figures  refer  to  the  moisture-free  leaves  in  each 
case : — 


Unprepared 
Leaves. 

Green 
Tea. 

Black 
Tea. 

Caflfeine  or  theine, 

Ether-extract, 

Hot-water  extract, 

Tannin  (as  gallotannic  acid),     , 
Other  nitrogen-free  extract, 

Crude  protein, 

Crude  fibre 

Ash 

Albuminoid  nitrogen, 

Caflfeine  nitrogen,  .--.      .... 

Amido-nitrogen, 

Total  nitrogen, 

S-30 
6-49 
50-97 
12-91 
27-80 
37-33 
10-44 
4-97 

4-11 
0-96 
0-91 
5-97 

3-20 
5'52 
53-74 
10-64 
31-43 
37-43 
10-06 
4-92 

3-94 
0-93 
113 

5-99 

3-30 

5-82 
47-23 

4-89 
35-39 
38-90 
10-07 

4-93 

4-11 
0-96 
1-16 
6-22 

The  proportion  of  ash  found  by  Kozai  is  remarkably  low,  but  it 
seems  not  impossible  that  this  is  characteristic  of  Japanese  teas, 
since  some  analyses  byj.  Takayama  {CJiem.  Neivs,\.  299)  show 
the  same  peculiarity. 

An  analysis  of  the  so-called  "  flower  of  tea,"  consisting  of  the 
hairs  of  the  leaf-buds  of  the  tea-plant,  has  been  published  by  T. 
B.  Groves  {Tear-Book  Pharm.,  1876,  page  610). 

James  Bell  {Foods,  i.  6)  gives  the  following  figures  as 
illustrating  the  composition  of  fair  representatives  of  black  and 
green  teas  of  commerce  :^ — 

determined  by  precipitation  with  cupric  acetate,  is  unusually  low.  Of  the 
extract,  from  15  to  16  per  cent,  was  precipi table  by  strong  alcohol.  A  nitrogen 
determination  on  the  precipitate  gave  a  result  corresponding  to  about  12  per 
cent,  of  albuminous  matters,  and  the  difference  was  regarded  as  gummy  sub- 
stances. The  chlorophyll,  wax,  and  resin  were  extracted  by  ether  from  the 
insoluble  matter,  after  drying,  and  the  residual  cellulose  purified  by  treatment 
with  nitric  acid,  potash,  and  alcohol. 

^  It  is  evident  that  in  these  analyses  some  constituent  was  determined  by 
difference,  but  it  is  not  stated  which.  Nor  does  Bell  state  the  method  used 
for  determining  the  tannin,  the  figures  for  which  are  highly  improbable, 
ivhile  other  of  his  descriptions  are  incomplete  or  obscure. 


COMPOSITION  OF  TEA. 


503 


Moisture, 

Caffeine,      .  

Albumin,  insoluble 

Albumin,  soluble, 

Extractive  by  alcohol,  containing  nitrogenous  matter, . 

Dextrin  or  gum, 

Pectin  and  pectic  acid, 

Tannin,       ....  

Chlorophyll  and  resin, 

Cellulose  and  insoluble  colouring  matter, 

Ash, 


Conejou 
(Black). 


8-20 

3-24 

17-20 

•70 

6-79 

2-60 
16-40 

4-60 
34-00 

6-27 


100-00 


Young  Hyson 
(Green). 


5-96 

2-33 

16-83 

-80 

7-05 
•50 

3-22 
27-14 

4^20 
25-90 

6-07 


100-00 


The  following  figures  are  given  by  J.  P.  Battershall  {Food 
Adulteration,  page  28)  as  the  results  of  the  analysis  by  American 
chemists  of  samples  representing  2414  packages  of  Indian  tea,  a 
class  remarkable  for  their  general  strength,  high  quality,  and  freedom 
from  adulteration : — 


Minimum. 

Maximum. 

Average. 

Moisture, 

5-83  per  cent. 

6-32  per  cent. 

5-94  per  cent. 

Insoluble  leaf,  . 

47-12       „ 

55-87        „ 

51  •91 

Extract, 

37-80        „ 
13-04 

40-35        „ 
18-87        „ 

38^84        „ 
15-32 

Tannin, 

Caffeine  or  theine,  . 

1-88 

3-24 

2-74 

Ash:— Total,    .       . 

5-05 

6-02 

5-61        „ 

Soluble  in  water. 

3-12        „ 

4-28        „ 

3-52 

Insoluble  in  acid. 

0-12 

0-30        „ 

0-18        „ 

The  following  figures,  obtained  by  C.  M.  C  a  i  n  e  s  in  the  author's 
laboratory,  are  interesting  as  indicating  the  character  of  the  first 
parcel  of  Natal  tea  ever  imported  into  England  :^ — Moisture,  8*36 

^  Natal  tea  must  not  be  mistaken  for  the  so-called  "Cape  tea"  and 
"Bush  tea,"  consisting  of  the  dried  leaves  and  Iwigs  of  certain  species  of 
Cyclopia.  According  to  H.  G.  Greenish  {Pharm.  Jour.,\Z'],  xi.  549,  569, 
832),    Cape   tea  is  destitute  of  caffeine  or  other  alkaloid,   but  contains  a 


604  CAFFEINE   IN   TEA. 

per  cent.  ;  insoluble  matter,  51-96  ;  hot-water  extract  (complete), 
39-68;  tannin  by  PbAg,  8-33;  tannin  by  CuA^,  S'SO;  caffeine 
by  Pblg  and  chloroform,  2*85;  total  ash,  6-14;  soluble  asli, 
3*56  ;  alkalinity  (K2O)  of  soluble  ash,  1*15  per  cent. 

Tlie  Moisture  contained  in  commercial  tea  varies  within  some- 
what wide  limits  (4-2  to  10-8  per  cent.);  but  the  range  is  far  less 
when  teas  of  the  same  class  are  compared.  Thus  G.  W.  W  i  g  n  e  r 
(Pharm.  Jour.,  [3],  vi.  361)  found  that  hyson  and  gunpowders,  both 
of  which  are  highly-dried  teas,  contained  the  smallest  proportions 
of  moisture  (4-84  to  6*55  per  cent.),  and,  after  drying  at  100°, 
absorbed  from  6*04  to  6-98  per  cent,  of  water  on  exposure  to  air. 
Congou  teas  showed  in  their  original  condition  an  average  of  8-50 
per  cent,  of  moisture,  and  never  wholly  regained  their  original 
weight  on  exposure  to  air  after  drying  at  100°.  The  average  pro- 
portion of  moisture  in  commercial  tea  is  about  7-7  per  cent.,  and 
the  usual  range  between  7  and  9  per  cent. 

Caffeine  or  Theine.  The  proportion  of  alkaloid  present  in  tea 
varies  considerably,  the  general  range  being  from  3-0  to  4-0  per  cent. ; 
but  the  experiments  of  Paul  and  Cownley  (page  492)  show  that  in 
Indian  and  Ceylon  tea  the  proportion  is  more  frequently  above 
4  per  cent,  than  below  that  figure ;  and  in  a  special  sample  of 
Himalayan  tea,  Zoller  found  as  much  as  4*94  per  cent,  of  caffeine,  in 
addition  to  a  small  proportion  of  what  was  apparently  theobromine. 
Unfortunately,  by  far  the  greater  number  of  published  determina- 
tions of  caffeine  are  quite  unreliable  (see  page  484),  and,  indeed, 
the  low  figures  recorded  suffice  to  indicate  their  inaccuracy  ;  and 
hence  any  deductions  as  to  the  relation  of  the  quality  of  tea  to 
the  proportion  of  alkaloid  present  must  be  received  with  great 
caution.  The  proportion  of  caffeine  is  not  generally  considered  to 
have  any  direct  relation  to  the  commercial  value  of  the  tea,  and 
the  tea-taster  takes  no  cognisance  of  it.  The  results  of  J.  F. 
Geisler  (page  506)  tend  to  show  that  the  proportion  of  caffeine 
which  passes  into  the  infusion  has  a  relation  to  the  quality  of  the 
tea,  the  superior  qualities  giving  up  their  alkaloid  to  water  more 
perfectly  than  the  inferior ;  but  as  the  whole  of  Geisler's  figures  for 
caffeine  (1*15  to  3-50  per  cent.)  are  probably  below  the  truth,  too 

glucosidal  body  called  cyclopin,  CgsHasO^s,  similar  to  cinchona- 
iiovatannic  acid,  and  yielding,  when  boiled  with  dilute  acid,  glucose, 
and  a  substance  of  the  formula  CigHgaOjo,  closely  resembling  cinchona-uova- 
icd.  Greenish  also  found  a  crystalline  substance  exhibiting  a  green  fluorescence 
in  alkaline  solutions,  and  probably  identical  with  the  cyclopic  acid 
j'feviously  described  by  A.  H.  Church  {Chem.  News,  xxii.  2);  and  like- 
wise a  third  substance  analogous  to  cyclopin,  and  apparently  an  oxidation- 
product  of  that  body.  Cape  tea  yielded  the  author  30  per  cent,  of  extract, 
and  on  ignition  left  3 '7  per  cent,  of  an  ash  containing  manganese. 


EXTRACTIVE   MATTER  OF  TEA.  o05 

iimch  stress  must  not  be  laid  on  this  conclusion;^  and  the  same 
remark  is  applicable  to  the  proposition  of  P.  D  v  o  r  k  o  v  i  t  c  h,  that 
tlie  higher  the  proportion  of  alkaloid  bears  to  that  of  the  tannin 
and  fermentation-products,  the  more  valuable  is  the  tea.  This 
varied  from  16"0  :  84  to  24'5  :75*5,  the  percentage  of  alkaloid  in 
the  tea  itself  ranging  from  2*14  to  3'45  per  cent. 

Chlorophyll.  When  either  green  or  black  tea  is  boiled  with 
alcohol  or  chloroform  a  solution  of  a  more  or  less  grass-green 
colour  is  obtained,  owing  to  the  extraction  of  chlorophyll.  E.  B. 
K  e  n  r  i  c  k  states  that  cheap  black  teas  yield  less  chlorophyll 
than  the  better  kinds,  and  believes  that  a  distinction  of  practical 
value  might  probably  be  based  on  a  colorimetric  determination. 

Extract.  By  the  term  "  extract,"  when  used  in  reference  to  tea 
analysis,  is  understood  the  sum  of  the  soluble  matters  extracted  from 
the  leaf  by  boiling  water.  It  includes  caffeine,  tannin,  albuminous 
matters,  gum,  dextrin,  colouring  matter,  mineral  matter,  &c., 
besides  other  less  important  constituents,  such  as  gallic  acid, 
boheic  acid,  oxalic  acid,  and  quercetin,  which  substances  are 
present  in  comparative  small  quantity,  if  at  all. 

The  proportion  of  extractive  matter  yielded  necessarily  varies 
with  the  method  used  to  exhaust  the  tea,  and  is,  of  course,  higher 
when  the  tea  is  powdered  and  the  treatment  with  water  long  con- 
tinued and  carried  to  an  extreme  than  when  the  whole  leaves  are 
used  and  the  tea  simply  infused  in  boiling  water.  The  latter 
method  commends  itself  when  the  object  is  to  study  the  character 
of  the  infusion  likely  to  be  yielded  in  practice,  while  the  former 
plan  gives  more  information  when  the  objection  is  the  detection  of 
adulteration. 

An  interesting  com|)arison  of  the  results  of  the  two  methods  has 
been  made  by  J.  F.  G  e  i  s  1  e  r,  who  has  published  an  extensive 
series  of  analyses  of  teas  obtained  direct  from  American  importers 
and  w^holesale  houses  {American  Grocer ,  Oct.  23,  1884;  Analyst 
ix.  220 ;  Prescott's  Organic  Analysis,  page  505  et  seq.).  The 
following  table  by  Geisler  shows  the  proportions  of  extract,  tannin, 
caffeine,  and  ash  which  passed  into  solution  when  various  repre- 
sentative commercial  teas  were  infused  under  precisely  the  same 
conditions  by  pouring  on  the  leaves  100  times  their  weight  of 
boiling  distilled  water,  and  allowing  the  liquor  to  "  draw  "  for  ten 
minutes.  The  ratio  which  the  dissolved  constituent  bore  to  the 
total  is  also  given. 

1  In  a  private  communication  to  the  author,  Mr  Geisler  states  that  the 
catfeine  was  determined  by  mixing  the  concentrated  decoction  with  magnesia 
and  sand,  and  exhausting  the  dry  mixture  with  chloroform  (compare 
page  486). 


606 


INFUSION   OF  TEA. 


Extract. 

Tannin.2 

Caf- 
feine. 

Ash. 

Kind  of  Tea. 

Wholesale 

Price  per  lb. 

in  Cents. 

Infu- 

Ratio 

to 
Total. 

Infu- 

Ratio 

to 
Total. 

Infu- 

sion. I'otaL 

sion. 

sion. 

sion. 

Fine  Ceylon  Pekoe  tips.i     . 

33-25 

76-6 

17-19 

75-3 

2-44 

3-44 

91-0 

Assam, 

m 

29-15 

73-5 

11-48 

60-8 

3-30 

3-80 

70-0 

Assam, 

22t 

28-57 

72-0 

9-50 

58-4 

2-75 

4-40 

79-5 

Finest  Moyune  Gunpowder, 

75 

37-32 

73-2 

16-79 

87-8 

2-95 

4-60 

55-8 

Common     Moyune     Gun-  \ 
powder,      ...       J 
Japan  Basket-fired, 

18 

28-07 

79-4 

9-26 

77-7 

1-67 

4-02 

66-1 

31-75 

75-6 

11-23 

74-5 

2-17 

4-27 

80-8 

Japan  Pan-fired,    . 

34-37 

79-6 

13-41 

94-4 

2-07 

3-67 

63-6 

Choicest  Formosa  Oolong,    . 

65 

33-62 

75-9 

12-91 

75-6 

2-50 

4-00 

71-3 

Choicest  Formosa  Oolong,    . 

53 

33-30 

73-7 

13-75 

68-5 

2-42 

3-97 

66-5 

Superior  Formosa  Oi^loiig,    . 

30 

29-00 

68-6 

9-63 

59-6 

2-12 

3-66 

62-3 

Medium  Am oy  Oolong, 

24 

27-40 

60-9 

1012 

56-0 

1-92 

3-72 

68-5 

Medium  Amoy  Oolong, 

215 

24-50 

60-5 

7-53 

55-6 

1-70 

3-25 

58-9 

Choicest  Moning  Congou,     . 

45 

24-25 

70-6 

5-46 

41-7 

2-87 

4-13 

73-7 

Superior  Moning  Congou,    . 

27 

21-55 

57-8 

4-44 

32  0 

2-77 

3-70 

63-6 

Medium  Moning  Congou,     . 

m 

21-02 

68-6 

5-55 

45-2 

2-33 

3-22 

58-3 

Good  Common  Kaisow  Con-  \ 
gou,     .        .       -               / 

17i 

23-25 

64-1 

4  05 

38-5 

2-35 

3-30 

59-9 

Common  Moning  Congou, 

15J 

19-50 

72-2 

4-50 

52-9 

1-95      2-88 

46-8 

1  Jour.  American  Cltem.  Soc,  xiii.,  Ho.  8. 

2  The  determinations  of  tannin  were  made  by  the  Lowenthal  method,  except  in  a  few 
nstances  in  which  the  cupric  acetate  method  was  employed. 

8  This  sample  is  considered  by  Geisler  to  have  been  adulterated,  though  its  appearance 
did  not  indicate  any  admixture  with  exhausted  leaves.— (Private  Communication  to 
Author.) 

A  comparison  of  these  figures  shows  that,  as  a  rule,  the  finer 
teas  yield  to  hot  water  larger  proportions  of  extract,  caffeine,  and 
ash  than  the  inferior  qualities.  On  an  average,  the  ash  of  the 
extract  exceeds  by  0'62  per  cent,  the  "soluble  ash"  obtained  by 
treating  the  ash  of  the  entire  tea  with  water.  The  proportion  of 
tannin  rises  and  falls  with  that  of  the  extract,  and  the  ratio  which 
the  dissolved  extract  and  tannin  bear  to  the  total  has  a  notable 
relation  to  the  price  of  the  tea. 

By  the  same  method  of  10  minutes  infusion  in  boiling-hot 
water,  E.  B.  Ken  rick  (Bulletin  No.  24,  Laboratory  of  Inland 
Revenue  Department,  Canada)  obtained  the  following  average 
results  from  commercial  samples  of  tea  : — 


Description  of  Teas. 

No.  of 
Samples. 

Aqueous 
Extract. 

Tannin 
Dissolved, 

Caffeine 
Dissolved. 

Ratio  of 
Aq.  Extract 
to  Tannin. 

Congou, 

Assam, 

Ceylon, 

Unclassed  Black, 

Japan, 

Gunpowder, 

Young  Hyson,   . 

10 
3 
2 
13 
18 
2 
5 

23-37 
38-53 
27-45 
23-76 
30-07 
28-55 
34-22 

5-18 
7-49 
7-85 
5-40 
9-38 
8 '00 
10-98 

2-65 
2-98 
2-68 
2-82 
2-45 
2-39 
2-52 

4-51 
3-81 
3-50 
4-40 
8-20 
3-57 
3-12 

INFUSION   OF  T'EA. 


507 


From  these  figures  it  appears  that  congou  teas  yield  less  extract 
than  green  and  Japan  teas,  while  Assam  and  Ceylon  teas  yield 
intermediate  results.  Not  only  do  the  Japan  and  green  teas  yield 
more  soluble  tannin  than  the  black,  but  the  proportion  of  tannin 
to  the  whole  extract  is  greater  in  the  former  kinds.  On  the  other 
hand,  the  black  teas  appear  to  yield  more  soluble  caffeine  than  the 
Japan  and  green  teas. 

The  following  figures  by  G  e  i  s  1  e  r  show  the  influence  of  the 
time  allowed  for  infusion  upon  the  proportion  of  the  constituents 
dissolved,  and  the  difference  in  the  result  caused  by  substituting  New 
York  water  (Croton  River,  of  4*96  degrees  hardness  per  100,000)  for 
distilled  water.  In  each  case  the  tea  used  was  the  finest  Formosa 
Oolong,  and  it  was  infused  in  100  parts  of  boiling  water: — 


Distilled  Water. 

Croton  Water. 

3  min. 

5  min. 

10  min. 

1  hour. 

5  min. 

10  min. 

Total  extract, 

25-97 

28-37 

30-87 

33-75 

27-47 

30-25 

Ash 

3-72 

3-80 

4  17 

4-33 

3-62 

4-13 

Extract  minus  ash,       .      , 

22  25 

24-50 

26-70 

29-42 

23-85 

26-12 

Tannin 

9-75 

11-23 

13-46 

14-94 

10-18 

10-60 

Caffeine, 

1-95 

2  65 

2  75 

2-85 

2-02 

2-82 

Alkalinity  of  infusion-ash  (= K2O), 

103 

1-08 

1-22 

1-28 

1-08 

1-15 

From  these  results  it  appears  that  infusion  in  distilled  water  for 
3  minutes  is  insufficient,  but  in  5  minutes  practically  as  good  a 
result  is  obtained  as  in  a  longer  time,  without  so  much  astringent 
matter  being  extracted.  ^^Hien  Croton  water  is  used,  10  minutes 
gives  a  materially  better  result,  so  far  as  caffeine  and  extract  are 
concerned,  while  the  proportion  of  tannin  is  not  increased  in  the 
same  proportion.  In  all  these  experiments  the  volatile  oil  is  left 
out  of  consideration,  though  it  is  to  this  constituent  that  the  flavour 
and  aroma  of  the  tea  is  due,  and  on  these  characters  the  commercial 
value  of  the  tea  materially  depends.  The  tannin  and  extractive 
matter  impart  astringency,  strength,  and  body  to  the  infusion. 
Caffeine,  being  almost  tasteless,  is  not  taken  into  account  by  tea- 
tasters,  though  physiologically  it  is  the  most  important  constituent 
of  tea. 

In  tasting  tea,  it  is  usual  to  infuse  the  weight  of  a  sixpenny 
piece  (43  grains)  of  the  sample  in  3  J  fluid  ounces  of  boiling  water, 
and  to  pour  off  the  infusion  after  standing  from  3  to  5  minutes, 
according    to    the    practice   of    the    taster.     The    infusion   is  not 


508 


TEA-TASTING. 


swallowed,  arid,  of  course,  no  sugar  or  milk  is  added.  In  the 
process  of  manufacture,  the  different  sized  leaves  are  separated  by 
sifting,  and  thus  broken  leaves  and  dust  are  obtained,  which, 
though  yielding  a  strong  infusion,  will  be  sold  at  a  lower  rate. 
Broken  or  powdered  tea  loses  its  aroma  more  rapidly  than  whole- 
leaf  tea.  Hence,  in  judging  of  the  commercial  value  of  a  tea,  the 
appearance  of  the  leaf  and  extent  to  which  it  is  damaged  are  taken 
into  account  as  well  as  the  characters  of  the  infusion.  The 
infusion  is  judged  by  its  strength  or  astringency,  its  flavour,  its 
colour,  and  its  odour.  The  strength  and  flavour  are  dependent 
on  the  age,  and  consequently  the  size  of  the  leaf,  and  the  time 
the  tea  has  been  kept  since  its  manufacture.  A  chemical  analysis 
will  indicate  the  strength,  but  not  the  flavour  of  the  infusion,  and 
hence  is  of  little  use  in  the  valuation  of  high-priced  teas ;  but  as 
in  medium  and  low-priced  teas  the  strength  is  of  as  great  or  more 
importance  than  the  flavour,  a  chemical  analysis  will,  in  such  cases, 
go  far  to  indicate  the  commercial  value  of  the  tea.  The  opinion 
formed  of  a  tea  by  a  professional  taster  is  sometimes  very  dijfferent 
from  that  to  which  a  chemical  examination  would  lead.^ 

It  is  comparatively  unusual  for  unmixed  tea  of  any  kind  to  be 
sold  retail.  Blending  of  several  kinds  is  very  generally  practised, 
and  when  conducted  judiciously  materially  improves  the  character 
of  the  tea. 

^  In  1874,  the  author  submitted  to  two  tea-tasters  of  considerable  experience 
a  series  of  samples  which  he  had  specially  prepared  to  test  their  ability  to 
recognise  adulterations  of  tea  by  the  taste.  The  following  were  the  opinions 
expressed : — 


Nature  of  Sample. 

A '  s  Opinion. 

B '  s  Opinion. 

No.  1.  70  per  cent,  of  No.  2 
and  30 per  cent,  exhausted 
and  redried  leaves. 

Tasted  "washed-out ; "   no 
doubt  from  presence  of 
exhausted  leaves. 

Very  poor  ;  contained  many 
exhausted  leaves :  ranked 
fifth. 

No.  2.  Genuine  black  tea  of 
fair  quality. 

Genuine. 

Passed  pure  ;  ranked  first 

No.  3.    No.    2    somewhat 
crushed. 

No.  4.  80  per  cent,  of  No.  2 
and  20  per  cent,  of  ex- 
hausted leaves,  to  which 
a  little  NaaCOa  was  added 
while  redrying. 

Mixed      with      exhausted 
leaves. 

Genuine ;  better  tea  than 
No.  3. 

Would  have  been  the  best, 
but  lacks  strength,  and  is 
therefore  suggestive  of 
exhausted  leaves.  Ranked 
third. 

Not  pure,  but  very  slightly 
adulterated  with  ex- 
hausted leaves.  Ranked 
fourth. 

No.  5.  80  per  cent,  of  No.  2, 
20  per  cent  of  exhausted 
leaves,  and  a  little  cate- 
chu. 

A  washed-out  tea  to  which 
some   astringent   matter 
had  been  added. 

Passed  pure,  and  ranked 
second. 

ADULTERANTS   OF  TEA.  609 

Adulterations  of  Tea. 

Before  the  passing  of  the  Adulteration  of  Food  Act  of  1872,  tea 
was  subject  to  adulterations  of  the  grossest  kind,^  most  of  which 
were  practised  prior  to  importation.  By  the  Sale  of  Food  and  Drugs 
Act  of  1875,  provision  was  made  for  the  examination  of  tea  by 
the  Custom  House,  and  the  exportation  or  destruction  of  very  bad 
paicels.2  Hence  the  tea  now  sold  in  the  United  Kingdom  is  rarely 
adulterated  in  the  gross  manner  which  was  formerly  common.^ 

The  adulterants  of  tea  may  be  conveniently  arranged  under  the 
following  four  heads : — 1.  Mineral  additions  used  for  increasing 
weight  or  bulk;  such  as  sand,  magnetic  iron  ore,  brass  filings. 
2.  Organic  additions  used  for  increasing  weight  or  bulk ;  such  as 
previously  infused  leaves,  and  leaves  other  than  those  of  the  tea 
plant,  as  slow,  elder,  willow,  &c.  3.  Adulterants  used  for  im^ 
parting  fictitious  strength,  by  increasing  the  astringency  or  deepen- 
ing the  colour  of  the  infusion ;  as  catechu,  sodium  carbonate,  borax. 
4.  Facings  and  colouring  materials ;  as  steatite,  prussian  blue,  indigo, 
turmeric,  graphite,  &c. 

The  practice  of  facing  tea,  formerly  very  common,  is  now  con- 
fined to  certain  kinds  of  green  tea,  especially  gunpowder,  and  the 

^  By  section  5  of  11  George  I.  cap.  30,  the  adulteration  of  tea  by  terra  japonica 
(catechu),  leaves  other  than  leaves  of  tea,  or  any  other  ingredients  whatever, 
was  punishable  by  forfeiture  and  a  fine  of  £100.  By  section  11  of  4  George  H. 
cap.  14,  a  penalty  of  £10  was  imposed  for  the  sale  of  every  pound  of  tea  which 
was  mixed,  coloured,  stained,  or  dyed  with  terra  japonica,  sugar,  molasses, 
clay,  logwood,  or  with  any  other  ingredients  or  materials  whatsoever. 

2  On  May  9,  1891,  W.  Cobden  Samuel,  the  chief  chemist  in  the  Custom 
House  Laboratory,  reported  that  437  samples  had  been  analysed  during  the 
year  1890,  viz.: — 84  samples  green  faced  tea;  10  green  not-faced  tea;  96  green 
caper  tea  ;  154  black  congou  tea  ;  64  black  dust  tea  ;  and  29  samples  of  siftings. 
Of  these,  384  samples  were  found  on  analysis  to  be  satisfactory.  Of  the  remain- 
ing 53  samples,  representing  516  packages  of  doubtful  and  unsound  teas,  1 
sample,  representing  5  packages,  was  admitted  to  home  consumption  ;  41 
samples,  representing  301  packages,  were  restricted  to  exportation,  owing  to 
the  presence  of  exhausted  leaves,  damage,  or  other  causes  within  the  Act ;  8 
samples,  representing  139  packages,  were  refused  admission,  as  unfit  for  human 
food  ;  and  3  samples,  representing  71  packages,  were  on  analysis  found  to  be 
teas  that  had  previously  been  imported,  and  ordered  to  be  exported.  They  were 
this  year  reimported  and  relabelled  as  new  season's  teas.  This  fact,  with  the 
analysis,  was  reported  to  the  Boanl  of  Customs,  and  the  whole  of  the  parcel  of 
71  packages  was  ordered  to  be  seized  under  the  Merchandise  Marks  Act. 

^  This  statement  does  not  apply  to  all  countries.  As  recently  as  1888, 
Wend  a  and  Wiorogorski  described  various  adulterations  they  had  met 
with  in  tea  sold  in  Warsiiw.  Bukowski  and  Aleksandrow  in  the  same 
year  found  as  much  as  40  per  cent,  of  ash  in  tea,  and  a  considerable  proportion 
of  brass-filings  in  one  sample. 


610  MINERAL  ADULTERANTS   OF   TEA. 

mineral  additions  for  increasing  weight  or  bulk  no  longer  include 
(so  far  as  the  United  Kingdom  is  concerned)  considerable  pro- 
portions of  magnetic  iron  ore,  &c.,  as  was  formerly  the  case. 

For  the  detection  of  mineral  adulterants,  and  to  obtain  certain 
other  knowledge,  the  tea  should  be  ignited,  and  the  proportions  of 
ash  soluble  in  water  and  acid  determined.  In  practice  this  is  best 
effected  by  igniting  6  grammes  of  the  tea,  in  its  ordinary  com- 
mercial condition,  in  platinum,  at  as  low  a  temperature  as  possible. 
When  the  carbon  is  burnt  off,  the  ash  will  have  a  distinct  green 
colour,  owing  to  the  formation  of  manganate.  The  ash  is  weighed 
and  boiled  with  water,  the  solution  filtered,  and  the  residue 
washed,  ignited,  moistened  with  ammonium  carbonate,  very  gently 
ignited,  and  weighed.  The  difference  between  the  weight  now 
found  and  that  of  the  total  ash  gives  that  of  the  ash  soluble  in 
water?-  The  insoluble  ash  is  next  boiled  with  strong  hydrochloric 
acid,  the  solution  diluted  with  hot  water,  filtered,  and  tlie  insoluble 
residue  washed,  ignited,  and  weighed.  It  consists  of  extraneous 
siliceous  matter,  such  as  sand,  fragments  of  quartz,  &c.,  and  in- 
soluble silicates,  such  as  steatite  from  the  facing  of  gunpowder  tea. 
If  titanic  iron  sand  be  present,  some  of  it  will  almost  certainly 
remain  undissolved,  and  present  the  appearance  of  jet-black 
magnetic  particles.^ 

The  solution  of  the  ash  soluble  in  water  should  be  titrated  with 

^  If  prefeiTed,  the  weight  of  the  soluble  ash  can  be  ascertained  directly,  by 
evaporating  the  solution  and  weighing  the  residue. 

2  The  adulteration  of  tea  with  magnetic  matter,  formerly  (in  the  experience 
of  the  author)  very  common,  is  now  apparently  nearly  obsolete,  a  clear  proof  that 
the  mineral  admixtures  were  not  due  to  accidental  causes.  Magnetic  matter 
is  best  detected  by  reducing  10  grammes  of  the  tea  to  powder  and  spreading  it 
in  a  thin  layer  on  a  sheet  of  smooth  paper.  A  magnet  or  electro-magnet  is 
then  applied  to  the  under-side  of  the  paper  and  moved  laterally,  with  its  poles 
in  contact  with  the  paper.  Any  magnetic  matter  may  thus  be  readily  drawn 
out  and  separated  from  the  tea.  It  is  next  boiled  with  water  for  a  few  minutes 
to  detach  adherent  organic  particles,  and  the  water  decanted.  The  residue  is 
then  dried  and  weighed,  and  examined  under  the  microscope  as  an  opaque 
object.  If  it  consists  of  magnetic  oxide  or  titanate  of  iron,  crystalline  facets 
will  probably  be  apparent,  the  bulk  of  the  object  having  a  jet-black  colour. 
Metallic  iron  would  be  distinguished  from  the  foregoing  ferruginous  minerals 
by  its  solubility  in  moderately  strong  nitric  acid  (sp.  gr.  1  -2)  with  evolution 
of  red  fumes,  and  by  its  precipitating  metallic  copper  from  a  warm  and  slightly 
acidulated  solution  of  cupric  sulphate. 

The  weighing  of  the  matter  actually  extracted  by  a  magnet  is  far  more 
satisfactory  than  the  estimation  of  the  iron  existing  in  the  tea.  Tea  naturally 
contains  a  small  proportion  of  iron,  but  it  only  amounts  to  about  3  per  cent, 
of  the  weight  of  the  ash,  or  about  018  per  cent,  of  the  entire  tea.  Of  course 
the  iron  in  this  form  is  not  affected  by  a  magnet,  the  use  of  which  has  the 


ASH   OF   TEA. 


611 


methyl-orange  or  litmus  and  standard  acid,  the  volume  used  being 
calculated  to  its  equivalent  of  potassium  oxide  (1  c.c.  of  j^  acid 
=  0-00471  gramme  of  KgO). 

The  analyses  of  a  very  large  number  of  teas  show  that  the  pro- 
portion of  soluble  ash  and  its  alkalinity  vary  with  the  age  of  the 
leaves,  the  figures  yielded  being  highest  with  young  leaves  and 
teas  of  high  quality.  The  total  ash  of  absolutely  pure  tea  rarely, 
if  ever,  exceeds  6  per  cent.,  but  some  licence  must  be  allowed  in 
dealing  with  commercial  samples.  Hence  in  1874,  the  Society  of 
Public  Analysts  suggested  8  per  cent,  as  the  maximum  limit  of 
total  ash  allowable  in  tea,  of  which  not  less  than  3  per  cent,  should 
be  soluble  in  water.  These  figures  refer  to  tea  previously  dried  at 
100°,  and  as  the  proportion  of  water  usually  lies  between  7  and 
8  per  cent.,  the  corresponding  limits  for  tea  in  its  ordinary  com- 
mercial condition  will  be  7 '40  and  2'77  per  cent,  respectively. 

Somewhat  more  recently  (1875),  G.  W.  Wigner  {Pharm, 
Jour.,  [3],  vi.  262,  281)  obtained  the  following  average  results  by 
the  analysis  of  sixty-seven  samples  of  commercial  tea  taken  from  the 
original  chests.  The  samples  embraced  forty-one  of  ordinary 
character,  eighteen  special  teas  of  high  price,  and  nine  samples  of 
caper.  Wigner  regarded  and  described  these  last  as  "genuine," 
and  they  were  clearly  free  from  any  large  proportion  of  mineral 
adulterants,  but  the  author  strongly  questions  whether  any  specimen 
whatever  of  caper  tea  really  deserves  the  description  of  "  genuine." 


Results  of  Analysis  of  Ash. 


Total. 


Siliceous 
Matter. 


Soluble 
in  Water. 


Alkalinity 
as  K2O. 


Samples  in  Commercial  State— 

Maximum,     .       .       .        . 

Minimum, 

Average 

Samples  after  drying  at  100°  C- 

Maximum 

Minimum,      .       .       .        . 

Average 


7-02 
5-17 
5-78 

7-42 
5-57 
6-33 


1-67 
0-04 
0-46 

1-76 
0-04 
0-50 


3-88 
2-64 
3-15 

4-16 
2-94 
3-45 


1-96 
1-08 
1-45 

2-11 
1-26 
1-54 


advantage  of  extracting  the  iron  in  the  form  in  which  it  actually  exists,  and 
production  in  court  if  necessary. 

In  1873  and  1874  the  author  frequently  found  from  5  to  8  per  cent,  of 
magnetic  matter  in  caper  tea,  and  at  that  time  the  use  of  the  magnet  for  its 
detection  v^as  well  known  to,  and  habitually  practised  by,  the  trade. 


512 


ASH   OF  TEA. 


The  asli  of  these  sixty-seven  samples  of  tea  had  the  following 
average  composition  : — 


Including 
Silica,  &c. 

Exclusive 
of  Silica,  .fee. 

Siliceous  matter 

Soluble  in  acid, 

Soluble  in  water, 

7-96  per  ceut. 
37-54 
54-50 

...    per  cent. 
40-79       „ 
59-21        „ 

100-00  per  cent.          100-00  per  cent. 

Alkalinity  of  soluble  ash,  as  K2O,     . 

25-09  per  cent. 

27-26  per  cent. 

James  Bell  {Foods,  i.  29,  31)  has  published  figures  agreeing 
with  those  of  Wigner.  The  proportion  of  soluble  ash  in  genuine 
teas  analysed  by  Bell  ranged  from  2*8  to  4*2  per  cent,  (calculated 
on  the  moisture-free  tea),  the  proportion  being  usually  between  3*2 
and  3 '6  per  cent.  In  one  instance  only  did  the  solubie  ash  fall 
below  3  per  cent.,  and  in  that  case  the  deficiency  was  very  trifling, 
the  proportion  being  2  "9 7  per  cent.  The  alkalinity  of  the  soluble 
ash  of  the  teas  examined  by  Bell  ranged  from  1*30  to  1'91  per 
cent,  of  KgO.  In  only  one  case  did  the  total  ash  reach  8  per  cent., 
while  the  insoluble  siliceous  matter  exceeded  1  per  cent,  in  a  few 
instances  only.  Bell's  results  are  fairly  in  accordance  with  the  wide 
experience  of  the  author  (see  Chem.  News,  xxix.  167,  189,  221).^ 

^  The  following  results  of  partial  analyses  of  average  samples  of  commercial 
black  teas,  as  ordinarily  imported,  have  been  communicated  to  the  author  by 
M.  J.  Sheridan,  Assistant  Chemist  in  H.M.  Customs  Laboratory.  The 
figures  refer  to  the  undried  tea  : — 


Ash. 

Description  of  Tea. 

Extract ;  on 
Whole 
Leaves. 

TotaL 

Soluble  in 
Water. 

Siliceous 
Matter. 

Indian  :— 

Orange  Pekoe,  , 

5-40 

8-20 

0-45 

40-49 

Assam  Pekoe,    . 

6-10 

3-30 

0-90 

39-32 

Souchong, 

5-70 

3-15 

0-60 

39-44 

Pekoe  Souchong, 

5-75 

3-25 

0-70 

38-78 

CETLON  :— 

Broken  Orange  Pekoe,     . 

5-50 

3-20 

0-20 

42-90 

Ceylon  Pekoe,  . 

5-40 

3-35 

0-25 

38-24 

Souchong, 

5-60 

3-40 

0-30 

37-98 

Japan  :— 

Sittings, 

6-12 

3-15 

0-95 

29-80 

Java  :— 

Congou,     .... 

5-00 

3  05 

0-50 

34-60 

Congou,     . 

7-65 

3-75 

1-05 

30-72 

China  :— 

Kaisow  Congou, 

5-70 

3-25 

0-50 

32-95 

Common  Congou,     . 

5-85 

2-95 

1-00 

31-71 

Souchong, 

5-60 

3-05 

0-65 

33-57 

Oolong,      .... 

5-65 

3-20 

0-70 

34-10 

Flowery  Pekoe, 

5-45 

3  05 

0-55 

35-70 

Port  Natal  :— 

Congou,     .... 

5-65 

3-10 

0-45 

34-80 

EXHAUSTED   TEA   LEAVES. 


513 


In  certain  cases  a  high  sokible  ash  does  not  indicate  a  high 
quality  of  tea.  This  liappens  when  the  ash  contains  a  notable  pro^ 
portion  of  sodium  chloride,  owing  to  the  tea  having  been  damaged 
by  sea-water  and  redried.  The  ash  of  pure  tea  contains  only  a 
trifling  proportion  of  sodium,  less  than  2  per  cent.,  and  the 
chlorine  does  not  exceed  1*1  per  cent.,  equivalent  to  about  1'8 
of  sodium  chloride,  representing  0"108  per  cent,  of  the  weight 
of  the  tea.  Wigner  (Pharm.  Jour.,  [3],  vi.  403)  found  3-08 
per  cent,  of  sodium  chloride  in  tea  which  had  been  a  fortnight 
under  sea-wnter  and  completely  soaked,  and  0'17  and  0'23  in 
samples  which  had  been  slightly  moistened. 

treviuu6lij  infused  or  exhausted  leaves  are  among  the  adultera- 
tions of  tea  most  difficult  to  detect,  especially  when  present  only 
in  moderate  proportion.  The  sophistication  of  tea  in  this  manner 
was  formerly  extensively  practised  in  England,  the  exhausted 
leaves  being  treated  with  gum  or  other  matters,  and  rolled  and 
redried  so  as  to  resemble  genuine  tea.^ 

The  treatment  of  tea  with  hot  water  necessarily  results  in  the 
removal  of  certain  of  the  ash-constituents,  especially  the  potassium 
salts  of  organic  acids.  Hence  the  exhausted  leaves  will  contain  a 
smaller  proportion  of  total  ash,  and  especially  of  ash  soluble  in 
water.  Tlie  extent  of  the  change  produced  by  infusion  will,  of 
course,  depend  on  the  perfection  of  the  exhaustion.  The  author 
found  in  a  mixture  of  infused  leaves  from  various  teas  4*30  of 
total  ash,  of  which  0*52  per  cent,  was  soluble  in  water.  James 
Bell  {Analysis  and.  Adulteration  of  Foods,  i.  29)  gives  the  follow- 
ing figures  obtained  by  the  analysis  of  the  ash  of  tea-leaves  which 
had  been  infused  in  the  ordinary  way  for  domestic  use,  and  after- 
wards redried  at  100°  : — 


Description  of  Tea. 

r 
Ash  of  Sample. 

Total. 

Siliceous             Soluble  in 
Matters.                Water. 

Alkalinity,  as 
K2O. 

Congou,      . 
Moning,     . 
Orange  Pekoe,  . 
Hyson, 
Souchong,  . 

3-92 
4-53 
3-77 
5-56 
4  12 

0-41 
0-95 
0-57 
1-40 
0-70 

0-54 
0-85 
0-68 
0-76 
0-81 

0-11 
0-28 
018 
0-21 
0-19 

^  Though  less  extensively  carried  on  than  formerly,  the  practice  of  redrying 
infused  tea-leaves  is  not  obsolete.     The  infused  tea-leaves  from  the  various 
bread    and    kindred    shops,    now  so  numerous    in    London,   are    regularly 
VOL.  III.  PART  II.  2   K 


614 


EXTRACT  OF   TEA. 


The  total  ash  of  the  foregoing  samples  averages  4*38,  and  the 
soluble  ash  0'73  per  cent. 

Exhausted  tea-leaves  are  also  indicated  by  the  deficient  extract 
(and  consequently  liigh  insoluble  matter)  and  low  proportion  of 
tannin.^  As  already  stated,  the  yield  of  extract  depends  materi- 
ally on  the  condition  of  the  tea,  more  complete  extraction  of  the 
soluble  matters  being  effected  when  the  powdered  tea  is  used 
than  when  the  exhaustion  is  effected  on  the  leaves  in  their  commer- 
cial condition.  For  the  purpose  of  detecting  adulteration,  the 
powdered  tea  should  always  be  used,  or  the  results  will  not  be 
fairly  comparable. 

The  determination  of  the  total  extract  and  insoluble  matter  of  tea 
is  best  effected  by  boiling  2  grammes  of  the  tea  in  a  state  of  powder 
with  100  C.C.  of  water  for  one  hour.  The  liquid  is  filtered  while 
hot,  the  residue  boiled  again  with  50  c.c.  of  water,  and  the  process 
repeated  as  long  as  colouring  matter  continues  to  be  extracted,  the 
liquid  being  poured  through  the  filter  previously  used.^  After 
cooling,  the  decoction  is  made  up  to  250  cc,  or  other  convenient 
measure,  and  an  aliquot  part  (one-fifth)  evaporated  to  dryness  for 
the  determination  of  the  extract.  The  filter  and  its  contents 
should  be  dried  at  100°,  and  the  insoluble  matter  detached  and 
weighed.     Very  constant  results  are  thus  obtainable. 

The  minimum  proportion  of  extract  yielded  by  genuine  tea 
exhausted  in  a  state  of  powder  was  fixed  by  the  Society  of  Public 
Analysts  in  1874  at  30  per  cent.  Assuming  the  presence  of  7 '5 
per  cent,  of  moisture,  this  leaves  62  per  cent,  for  the  maximum 
proportion  of  insoluble  matter.  This  figure  covers  almost  all  legiti- 
mate variations  in  tea,  and  is  considerably  in  excess  of  the  propor- 
tion yielded  by  green  tea,  the  insoluble  matter  from  which  averages 
42  per  cent.,  while  in  black  teas  the  average  is  only  about  50  per 

bought  up  and  redried  ;  and  the  leaves  of  the  tea  infused  by  tea-tasters  are 
systematically  preserved  and  sold  for  the  same  purpose. 

^  J.  M.  Eder  obtained  the  folloviring  figures  by  the  analysis  of  teas  adul- 
terated with  exhausted  leaves  purchased  in  small  shops  in  the  suburbs  of 
Vienna  : — 


Tannin 
(by  Cul^)- 

Extract. 

Total  Ash. 

Soluble  Ash. 

Riissian  tea,     . 
Bloom  tea,       .      . 
Bloom  tea,       .      . 

6-60 
4-91 
5-13 

18-4 
15-3 
14-6 

4-76 
S-34 
4-51 

0-85 
0-54 
0-90 

*  The  decoction  of  some  teas  filters  very  slowly,  and  it  is  necessary  to  strain 
the  liquid  through  fine  muslin  instead  of  filtering  it  through  paper. 


EXTRACT  OF  TEA.  ,515 

cent.  In  the  case  of  old-leaf  Congou  teas  containing  much  stalk, 
and  which  have  been  stored  for  some  time,  the  extract  may  occa- 
sionally fall  to  30  per  cent.,  corresponding  to  62 J  per  cent,  of 
insoluble  matter.  In  judging  a  tea  by  the  proportion  of  extract 
or  insoluble  matter,  it  is  very  desirable,  when  possible,  to  take  into 
account  the  character  of  the  sample.  Thus  young  leaves  (which 
are  to  some  extent  indicated  by  their  size)  yield  a  notably  higher 
extract  than  fully  grown  or  old  leaves,  or  specimens  containing 
a  considerable  proportion  of  stalk. 

G.  W.  Wign  e  r  has  recorded  the  proportions  of  extract  yielded 
by  a  sample  of  tea  in  powder  when  boiled  with  different  quantities 
of  water.  In  each  case  the  tea  was  boiled  with  the  water  under  a 
reflux  condenser  for  one  hour,  the  decoction  cooled,  filtered,  and 
evaporated  to  dryness. 

A.  1  part  of  tea  in  200  parts  of  water  yielded  .54  10  ;  er  cent,  of  extract. 

B.  ..         ,.        100  ,,  ,,  30-55        „  „ 

C.  „         ..  50  „  ,,  27-55        „  „ 

D.  „  „  20  „  „  22-90  ■ 


£.    Exhausted  leaves  from  expt.  D  in  20      \    j,.,.. 

parts  water,  .  .  .         it 

3-75  I 

1.75  j 


36-67 


F.  ..  .,  E 

G.  „  „  F 


Even  after  four  boilings  with  20  parts  of  water,  the  tea  was  not 
completely  exhausted.  Hence  Wigner  preferred  to  determine  the 
extract  by  boiling  the  powdered  tea  once,  for  one  hour,  with  100 
parts  of  water,  instead  of  repeatedly  exhausting  with  smaller  quan- 
tities. Operating  in  this  manner  he  obtained  proportions  of  extract 
ranging  from  26*15  to  44*85  per  cent.,  the  average  being  35*70  per 
cent.,  containing  46 3  of  ash.^ 

The  determination  of  tannin  in  tea  affords  valuable  information 
respecting  the  probable  presence  of  previously  infused  leaves  or 
extraneous  tannin  matters,  such  as  catechu.  This  is  best  effected 
in  the  aqueous  decoction  obtained  by  exhausting  the  sample  with 
boiling  water,  as  required  for  the  determination  of  the  extract. 

The  tannin  may  be  estimated  by  H.  R.  Procter's  modification 
of  Ldwenthal's  process,  as  described  in  Vol.  III.  Part  I.  page 
110.  A  volume  of  the  above  decoction,  corresponding  to  0*04 
gramme  of  tea,  may  be  taken  for  the  original  titration  with  perman- 
ganate j  and  of  the  decoction  deprived  of  tannin  a  volume  correspond- 

^  The  ash  of  the  soluble  extract  of  tea  always  exceeds  by  a  considerable 
amount  the  proportion  of  tea-ash  soluble  in  water,  doubtless  owing  to  the 
presence  in  tea  of  soluble  salts  of  calcium  and  magnesium  with  organic  acids, 
which  salts  on  ignition  are  converted  into  calcium  carbonate  and  magnesia, 
and  thus  become  insoluble  in  water. 


516  FERMENTATION   PRODUCTS   IN    TEA. 

ing  to  0"080  gramme  of  tea.  The  tannin  of  tea  is  stated  by  some 
chemists  to  be  gallotannic  acid,  and  by  others  to  be  identical  with 
that  of  oak-bark.  The  reduction-equivalent  of  the  latter  is  almost 
identical  with  that  of  crystallised  oxalic  acid,  so  that  the  weight 
of  this  substance  corresponding  to  the  volume  of  permanganate 
decolorised  gives  without  calculation  that  of  the  tannin  present. 

The  process  of  fermentation  to  which  black  tea  has  been  sub- 
jected undoubtedly  causes  modification  of  the  tannin,  with  forma- 
tion of  dark-coloured  insoluble  matter.  The  author  found  that 
a  tincture  of  green  tea  precipitated  tincture  of  ferric  chloride  bluish 
black,  like  nut-galls,  while  the  tincture  of  black  tea  gave  a  green 
colour  with  iron,  just  as  catechu  does. 

A  modification  of  the  permanganate  process,  which  appears  to 
possess  some  advantages  for  the  examination  of  tea,  has  been 
described  by  P.  Dvorkovitch  {Ber.,  xxiv.  1945 ;  Jour.  Cliem. 
Soc,  Ix.  1302),  who  aims  not  only  in  estimating  the  tannin  but 
also  the  proportion  of  fermentation-products  formed  in  the  process 
of  fermentation  to  which  l)lack  tea  has  been  subjected.  For  this 
purpose  he  treats  10  grammes  of  finely-powdered  tea  with  three 
successive  quantities  of  200  c.c.  of  boiling  water,  five  minutes 
being  allowed  for  each  digestion.  The  residue  is  then  boiled  twice 
with  200  c.c.  of  water,  or  until  the  last  extract  is  almost,  if  not 
entirely,  free  from  colour,  when  the  decoction  is  diluted  to  1  litre. 
Forty  c.c.  of  this  solution  is  then  diluted  to  500  c.c.  with  water, 
and  treated  with  25  c.c.  of  indigo-carmine  solution^  and  25  c.c.  of 
dilute  sulphuric  acid  (200  grammes  of  H2SO4  per  litre).  The 
liquid  is  then  titrated  with  a  standard  solution  of  potassium  per- 
manganate (containing  approximately  2*6  grammes  per  litre),  and 
of  such  strength  that  130  c.c.  are  equivalent  to  100  c.c.  of  deci- 
normal  oxalic  acid  (6 "3  grammes  crystallised  acid  per  litre).  The 
mode  of  adding  the  permanganate  is  important,  and  Dvorkovitch 
recommends  that  in  the  titration  of  the  indigo-carmine  18  c.c. 
should  be  added  at  the  rate  of  2  to  3  drops  per  second,  and  the 
remainder  at  the  rate  of  1  drop  per  second ;  and  that,  in  the  titra- 
tion of  the  tea  solution  mixed  with  indigo-carmine,  23  c.c.  of  the 
permanganate  should  first  be  run  in,  the  addition  continued  at  the 
rate  of  2  to  3  drops  per  second,  and  finally  1  drop  per  second 
added  until  the  reaction  is  complete.  If  more  than  38  c.c.  be 
required,  a  small  quantity  of  tea  infusion  should  be  used.  To 
estimate  the  fermentation-products^  80  c.c.  of  the  tea  infusion  is 
mixed  with  20  c.c.  of  baryta- water  (containing  4  grammes  of  baryta 

^  Prepared  by  mixing  50  grammes  of  pure  indigo-carmine  paste  with  water, 
adding  50  grammes  of  sulphuric  acid  and  1  litre  of  water,  filtering,  and  dilut- 
ing till  25  c.c  require  20  c.c.  of  the  standard  permanganate  for  oxidation. 


TANNIN   IN   TEA.  517 

per  100  c.c),  the  liquid  filtered,  and  50  c.c.  of  the  filtrate  (repre- 
senting 0*4  gramme  of  the  tea)  diluted  with  500  c.c.  of  water, 
mixed  with  25  c.c.  of  dilute  sulphuric  acid  and  25  of  the  indigo - 
carmine  solution,  and  titrated  with  permanganate.  18  c.c.  should 
be  run  in  first  of  all,  then  2  or  3  drops  per  second  added,  and  finally 
1  drop  per  second  till  the  end  of  the  reaction.  Tlie  volume  of 
permanganate  required,  less  that  reduced  by  the  imligo  solution, 
represents  that  required  for  the  oxidation  of  the  fermentation- 
products  of  0*4  gramme  of  tea.  According  to  Dvorkovitch,  the 
joint  weight  of  tannin  and  fermentation-products  is  obtained  by 
multiplying  the  weight  of  oxalic  acid  equivalent  to  the  measure  of 
permanganate  required  for  their  oxidation  by  3 13,  since  63 
grammes  of  oxalic  acid  correspond,  according  to  Dvorkovitch's 
experiments,  to  31 '3  grammes  of  tea-tannin  (as  compared  to  62 '3  of 
quercitannic  acid  !).  Employing  this  process,  he  found  from  8*84 
to  10'55  per  cent,  of  tannin,  and  from  0*90  to  r88  of  fermentation- 
products,  in  teas  of  the  first  crop  of  1890;  and  lie  concludes  that 
the  higher  the  proportion  of  cafi'eine  to  the  total  amount  of  tannin 
and  fermentation-products,  the  more  valuable  is  the  tea. 

The  Lowenthal  process  distinguishes  the  tannic  acid  from  the 
small  quantity  of  gallic  acid  also  present  in  tea,  but  as  the  astringent 
character  of  the  infusion  is  due  to  both  these  substances,  a  method 
which  will  estimate  the  total  amount  of  astringent  matter,  without 
distinction  of  its  nature,  is  in  some  respects  preferable  to  a  process 
that  gives  merely  the  amount  of  tannin,  while  ignoring  the  gallic 
acid.  Such  a  process  was  devised  by  F.  W.  Fletcher  and  the 
author  in  1874  (Chem.  News,  xxix.  169,  189),  and  was  based  on 
the  precipitation  of  the  tea  infusion  by  lead  acetate,  and  the  use 
of  an  ammoniacal  solution  of  potassium  ferricyanide  to  indicate  the 
complete  precipitation  of  the  astringent  matters.  In  practice,  5 
grammes  of  neutral  acetate  of  lead  should  be  dissolved  in  distilled 
water,  and  diluted  to  1  litre,  and  the  solution  filtered  after  stand- 
ing. The  indicator  is  made  by  dissolving  0'050  gramme  of  pure 
potassium  ferricyanide  in  50  c.c.  of  water,  and  adding  an  equal 
bulk  of  strong  ammonia  solution.  This  reagent  gives  a  deep  red 
coloration  with  gallotannic  acid,  gallic  acid,  or  an  infusion  of  tea. 
One  drop  of  the  solution  will  detect  0*001  milligramme  of  tannin, 
or  O'OOl  gramme  dissolved  in  100  c.c.  of  water.  In  carrying  out 
the  process,  three  separate  quantities  of  10  c.c.  each  of  the  standard 
lead  solution  should  be  placed  in  beakers,  and  each  quantity  diluted 
to  about  100  c.c.  with  boiling  water.  A  decoction  made  from  2 
grammes  of  powdered  tea  in  250  c.c.  of  water  (the  same  as  is  used 
for  determining  the  extract)  is  added  from  a  burette,  the  first  trial 
quantity  receiving  an  addition  of  12,  the  second  15,  and  the  third 


518  TANNIN   IN  TEA. 

18  CO.;  or  if  green  tea  be  under  examination,  8,  10,  and  12  c.c 
may  be  preferably  employed.  Portions  (1  c.c.)  of  these  trial 
quantities  are  passed  through  small  filters,  and  tlie  filtrates  tested 
with  ammoniacal  ferricyanide  solution. 

The  approximate  volume  of  tea  decoction  required  is  thus  easily 
found,  and  after  repeating  the  test  nearly  the  requisite  measure  can 
be  at  once  added.  In  this  case  about  1  c.c.  of  the  liquid  should 
be  removed  with  a  pipette,  passed  through  a  small  filter,  and  drops 
of  the  filtrate  allowed  to  fall  on  to  spots  of  the  indicating  solution 
previously  placed  on  a  porcelain  slab.  If  no  pink  coloration  is 
observed,  another  small  addition  of  the  tea  decoction  is  made,  a 
few  drops  of  the  liquid  filtered  and  tested  as  before,  and  this  pro- 
cess repeated  until  a  pink  colour  is  observed.  The  greatest  delicacy 
is  obtained  when  the  drops  of  filtered  solution  are  allowed  to  fall 
directly  on  to  the  spots  of  the  indicator,  instead  of  observing  the 
point  of  junction  of  the  liquids. 

The  volume  of  tea  solution  it  is  necessary  to  add  to  100  c.c.  of  pure 
water,  in  order  that  a  drop  may  give  a  pink  reaction  with  the  indicator, 
should  be  subtracted  from  the  total  amount  run  from  the  burette. 

The  foregoing  process  is  simple,  and  gives  very  concordant 
results;  but  the  repeated  filtrations  requisite  for  the  observation 
of  the  end-reaction  are  apt  to  be  tedious.  It  is  difiicult  to  obtain 
pure  tannin  for  setting  the  lead  solution,  and  hence  it  is  preferable 
to  abandon  the  attempt  and  make  pure  lead  acetate  the  starting- 
point.  The  author  found  that  10  c.c.  of  the  lead  solution  would 
precipitate  O'OIO  gramme  of  the  purest  gallotannic  acid  he  could 
obtain.  Hence,  if  aU  the  weights  and  measures  above  mentioned 
be  adhered  to,  the  number  of  c.c.  of  tea  decoction  required,  divided 
into  125,  will  give  the  percentage  of  tannin  and  other  precipitable 
matters  in  the  sample.  The  proportion  found  in  undried  black  tea 
by  F.  W.  Fletcher  and  the  author  ranged  from  8'5  to  11*6  per  cent., 
with  an  average  of  1 0  per  cent.  A  sample  of  brown  catechu  tested 
by  the  lead  process  gave  a  result  corresponding  to  the  presence  of 
119  per  cent,  of  tannin  {sic).     (See  also  page  491.) 

Another  simple  method  for  the  determination  of  tannin  is  that 
of  J.  M.  Eder  {Dingl.  Polyt.  Jour.,  ccxxix.  81),  which  consists 
in  precipitating  the  boiling  decoction  of  2  grammes  of  tea  with 
excess  of  a  5  per  cent,  solution  of  cupric  acetate.  The  precipitate 
is  separated  by  filtration,  washed,  dried,  and  ignited.  The  resultant 
cupric  oxide,  CuO,  can  be  moistened  with  nitric  acid,  re-ignited  and 
weighed  as  such ;  or  re-ignited  with  sulphur  in  a  closed  ciucible, 
and  thus  converted  into  an  equal  weight  of  non-hygroscopic  cuprous 
sulphide,  CugS.  The  weight  obtained,  multiplied  by  1-305,  gives 
that  of    the    tannin    precipitated.     The   method   is   said   to  give 


CATECHU   IN  TEA.  519 

results  correct  to  within  0*2  to  0"3  per  cent. ;  but  any  pectous 
bodies  should  be  previously  separated,  if  present  in  quantity,  by 
precipitation  with  alcohol.     By  this  method  Eder  found  an  average 

01  about  10  per  cent,  of  tannin  in  twenty-five  samples  of  black 
tea,  and  12  to  12 J  in  green  and  yellow  tea.  S.  J  ank  e,  by  the 
same  process,  found  from  6 "9  to  9"1  per  cent,  of  tannin  in  black 
tea  (eighteen  samples),  and  8 "6  to  9*9  in  green.  Cupric  acetate  may 
be  extemporised  by  mixing  a  solution  of  cupric  sulphate  with  excess 
of  sodium  acetate. 

C.  M.  Gaines  (page  491)  obtained  results  by  Eder's  method 
closely  agreeing  with  those  yielded  by  the  same  samples  with  the 
lead  process,  and  hence  the  proportion  of  gallic  acid  in  tea  is 
probably  very  insignificant. 

In  the  case  of  caper  and  lie  teas,  the  astringency  is  often  very  high, 
owing  to  an  admixture  of  extraneous  tannin  matters ;  but  the 
evidence  of  the  presence  of  such  additions  afforded  by  the  determina- 
tion of  the  tannin  of  tea  is,  of  course,  merely  inferential.  Strong 
infusions  of  genuine  tea,  with  the  exception  of  some  kinds  from 
India,  are  generally  quite  clear,  and  do  not  become  muddy  on 
cooling.  Tea  adulterated  with  catechu  gives  an  infusion  which 
quickly  becomes  turbid  on  cooling.  More  direct  proof  of  the 
presence  of  catechu  may  be  afforded  by  the  following  test  devised 
by  the  author,  which,  however,  should  always  be  applied  to  the 
suspected  tea  side  by  side  with  a  genuine  specimen  : — One  gramme 
of  the  pure  tea  and  an  equal  weight  of  the  suspected  sample  are 
infused  in  100  c.c.  of  boiling  water,  and  the  strained  liquid  pre- 
cipitated while  boiling  with  a  slight  excess  of  neutral  lead  acetate. 
Twenty  c.c.  of  the  filtrate  from  pure  tea  (which  should  be  colour- 
less) when  treated  with  a  few  drops  of  silver  nitrate  solution  (avoid- 
ing excess),  and  cautiously  heated,  gives  only  a  very  slight  greyish 
cloud  or  precipitate  of  reduced  silver ;  but  the  same  tea  containing 

2  per  cent,  of  catechu  (purposely  added)  gives  a  copious  brownish 
precipitate,  the  liquid  acquiring  a  distinctly  yellowish  tinge.  With 
a  somewhat  larger  proportion  of  catechu,  the  filtrate  from  the  lead 
precipitate  gives  a  bright  green  colour  on  adding  one  drop  of 
dilute  ferric  chloride,  while  the  solution  of  pure  tea  gives  only  a 
slight  reddish  colour  due  to  the  presence  of  acetate.  On  allowing 
this  liquid  to  stand,  the  adulterated  tea  gives  a  precipitate  of  a 
greyish  or  olive-green  colour,  the  pure  tea  undergoing  no  change. 

These  tests,  which  depend  on  the  properties  of  catechuic  acid, 
together  with  the  excessive  proportion  of  astringent  matters  (as 
shown  by  the  lead  process),  render  the  detection  of  any  consider- 
able proportion  of  catechu  tolerably  certain ;  but  a  means,  of 
detecting  small  additions  is  still  a  desideratum. 


520 


CAPER  AND  LIE  TEA. 


Catechu  is  usually  introduced  in  the  forms  of  caper  and  lie  tea, 
but  appears  to  have  been  sometimes  added  in  a  separate  state,  to 
impart  additional  '*  roughness "  or  to  cover  the  presence  of  ex- 
hausted leaves. 

Caper  is  a  name  applied  to  tea  which  has  been  made  up  into 
small  glossy  granular  masses  by  the  aid  of  gum  or  starch.  Some 
years  ago  the  caper  tea  from  the  Canton  district  was  invariably 
adulterated  with  sandy  and  magnetic  matter,  and  often  with 
catechu  or  other  extraneous  astringents,  together  with  foreign 
leaves.^  Notwithstanding  the  conviction  of  Wigner  and  some 
other  authorities  that  genuine  caper  tea  exists,  the  author  believes 
it  to  be  invariably  a  factitious  article. 

Lie  tea  is  the  name  given  to  a  fraudulent  mixture  consisting  of 
sweepings  and  dust  of  tea  and  other  leaves,  mixed  with  clay,  sand, 
iron  ore,  &c.,  and  made  into  irregular  masses  by  means  of  gum  or 
starch.  When  put  into  hot  water,  lie  tea  disintegrates  and  falls 
to  powder.  The  iodine  test  for  starch  may  be  applied  after  acidi- 
fying tlie  cold  liquid  with  sulphuric  acid,  and  decolorising  with 
])ermanganate.  The  ash  of  lie  tea  is  sometimes  as  high  as  30  to 
40  per  cent. 

The  insoluble  matter  and  extract  of  lie  and  caper  tea  are  very 
variable ;  but  the  former,  exclusive  of  mineral  matter,  is  usually 
considerably  below  the  proportion  yielded  by  genuine  tea.  The 
gum 2  in  caper  tea  often  amounts  to  15  or  20  per  cent.,  while  the 
i?olubIe  ash  is  often  less  than  2  per  cent. 

The  following  figures  show  the  results  to  be  expected  from  the 
analysis  of  factitious  tea  : — 


A. 

B. 

C. 

Observer, 

J.  Bell. 

J.  M.  Eder. 

A.  B.  Hill. 

Description,   , 

"  Mahloo  mixture." 

Black  tea. 

Green  tea. 

Extract, 

22-40 

37-00 

Tauniii, 
Total  Ash,  . 

9-97 

19-77 

(Catechu  detected) 

3-07 

Catechu 

detected. 

12-10 

Magnetic  and  sandy  matter, 

4-31 

6-00 

Soluble  Ash,  . 

1-54 

1-12 

1-29 

Alkalinity,  as  K2O,  . 

0-17 

... 

0-13 

^  At  the  present  time  (August  1892),  Canton  capers  are  frequently  loaded 
with  from  3  to  5  per  cent,  of  sand,  &c.,  but  they  rarely  appear  in  the  home 
market,  being  stopped  by  the  Customs,  or  purposely  imported  for  future  ex- 
portation (M.  J.  Sheridan). 

'^  The  gum  is  determined  by  concentrating  the  aqueous  decoction  of  the  tea 


FACTITIOUS  TEA. 


521 


The  following  analyses  of  samples  of  spurious  tea,  received  from 
the  U.S.  Consuls  at  Canton  and  Nagasaki,  are  by  J.  P.  Batter- 
shall  {Food  Adulteration^  page  28).  No.  1  consisted  of  partially 
exhausted  and  refired  leaves  known  as  "  cliing  suey  "  (clear  water), 
a  name  apparently  referring  to  the  character  of  the  infusion. 
No.  2  was  a  sample  of  "lie-tea"  made  from  wampan  leaves.  No.  3 
was  a  mixture  of  10  per  cent,  of  green  tea  with  90  per  cent,  of 
lie-tea,  sometimes  sold  as  "Imperial"  or  "Gunpowder"  tea. 
No.  4  was  a  sample  of  "scented  caper,"  consisting  of  tea-dust 
made  up  into  little  shot-like  pellets  by  means  of  "  Congou  paste  " 
(boiled  rice) : — 


No.  1. 


No.  2. 


No.  3.        No.  4. 


Insoluble  leaf, 

Extract  (complete), 

Gum,     . 

Tannin, . 

Caffeine, 

Ash :— Total, 

Soluble  in  water. 
Insoluble  in  acid, 


70-60 
7-73 

10-67 
8-13 

0-58 
8-62 
0-64 
3-92 


70-65 
14-00 
7-30 
801 
none 
8-90 
1-86 
3-18 


67-00 
12-76 
11-00 
14-50 
0-16 
7-95 
3-00 
1-88 


60-10 

22-10 

11-40 

15-64 

0-12 

12-58 

3-84 

6-60 


Logwood  is  mentioned  by  Eder  as  an  adulterant  of  tea.  To 
detect  it,  he  steeps  the  tea  in  cold  water.  If  logwood  be  present, 
the  resultant  solution  is  changed  to  a  bright  green  on  adding  a 
little  sulphuric  acid,  and  to  blackish-blue  by  a  solution  of  neutral 
chromate  of  potassium. 

Facings  and  colouring  materials  were  formerly  almost  invariably 
present  in  green  tea,^  the  object  being  to  impart  a  hue  demanded 
by  custom  but  not  naturally  possessed  by  the  leaf.  Colouring 
matters  have  been  extensively  employed  for  transforming  black 
tea  of  low  quality  into  superior  green. 

In  the  case  of  Roberts  v.  Egerton,  heard  before  the  Court  of 

almost  to  ail  extract,  treating  the  residue  with  strong  spirit,  and  filtering 
and  washing  with  spirit.  The  precipitate  is  rinsed  off  the  filter  with  hot 
water,  and  the  solution  evaporated  to  dryness  at  100°.  The  residue  is 
weighed,  ignited,  and  the  ash  weighed.  The  loss  is  regarded  as  "gum," 
but  is  liable  to  be  in  excess  of  the  truth  from  the  presence  of  albuminous 
matters. 

^  It  is  a  fact  well  known  to  the  trade  that  for  many  years  a  certain  firm  of 
tea  merchants  used  some  method  of  removing  the  facing  after  the  arrival  of 
the  tea  in  this  country. 


522^  FACINGS  OF  TEA. 

Queen's  Bench  in  187  4,  Mr  Justi(;e  Blackburn  decided  that  the  facing 
of  green  tea  with  gypsum  and  prussian  blue  was  an  adulteration, 
because  natural  green  tea  could  be  obtained  without  such  means.-'- 

If  a  faced  tea ,  be  examined  under  the  microscope  as  an  opaque 
object,  the  nature  of  the  facing  materials  may  often  be  recognised. 
On  treating  a  faced  tea  with  warm  water,  the  colouring  matters 
become  detached',  and  the  small  portions  rising  to  the  surface  may 
be  floated  on  to  a  glass  slide  and  at  once  examined  under  a  micro- 
scope, while  the  bulk  of  the  facing  is  obtained  as  a  sediment  when 
the  strained  liquid  is  allowed  , to  stand. ^ 

Foreign  leaves  in  tea  are  legitimately  present  in  small  proportion 
(1  to  3  per  cent.)  to  impart  bouquet,^  but  larger  admixtures  can 
simply  be  regarded  as  due  to  adulteration.  Sloe,  elder,  and  willow 
leaves  have  been  (formerly)  met  with  in  England  as  adulterants  of 
tea.*  Among  the  recently-found  leaves  added  abroad,  and  stopped 
by  the  Customs,  are  those .  gf  ChlorantJms  inconspicuus,  Camellia 
sasanqua,  Eurya  Chinensis,  and  sloe.^    In  the  recognition  of  foreign 

^  The  teas  consumed  by  the  Chinese  and  Japanese  themselves  are  not  faced. 
According  to  Y.  Kozai  the  maximum  proportion  of  facing  in  the  green  tea 
of  Japan  is  about  0*4  per  cent. 

^  This  deposit  often  has  a  distinctly  greenish  colour  from  the  presence  of 
prussian  blue  or  indigo.  Indigo  may  be  recognised  by  its  behaviour  with  nitric 
acid.  Prussian  blue  is  best  detected  by  warming  the  sediment  with  caustic 
alkali,  filtering,  strongly  acidulating  the  filtrate  with  hydrochloric  acid,  filter- 
ing again  if  necessary,  and  testing  the  clear  liquid  for  ferrocyanide  with  ferric 
chloride.  On  treating  tlie  sediment  with  the  alkali  it  is  sure  to  turn  brown, 
but  this  change  must  not  be  regarded  as  aTi  indication  of  the  presence  of  prus- 
sian blue.  The  residue  left  after  treatment  with  the  caustic  alkali  should  be 
treated  with  hydrochloric  acid,  when  the  insoluble  portion  will  usually  consist 
of  steatite  or  other  Tnagnesian  silicate,  the  use  of  which  gives  the  tea  a  peculiar 
smooth  appearance  and  slippery  feel.  Calcium  sulphate  is  often  employed  for 
facing  tea.  Caper  tea  is  often  glazed  with  graphite.  Turmeric  has  been 
detected  by  some  observers,  but  in  the  experience  of  the  author  the  yellow 
colouring  matter  has  generally  been  of  a  ferruginous  nature. 
^  As  a  rule,  the  odoriferous  leaves  are  not  allowed  to  remain  in  the  tea,  but 
having  imparted  their  characteristic  fragrance  to  the  tea  are  removed  previously 
to  packing. 

*  From  the  result  of  a  parliamentary  inquiry  held  in  1835,  it  appeared  that 
upwards  of  four  million  pounds  of  factitious  tea  were  annually  prepared  in  this 
country  from  sloe  leaves,  and  used  to  adulterate  China  tea.  Up  till  within  a 
few  years  of  that  date  this  illicit  practice  was  carried  on  secretly,  but  subse- 
quently a  patent  was  obtained  for  the  preparation  of  British  leaves  as  a  substi- 
tute  for  tea,  and  an  extensive  manufactory  was  established  for  this  purpose. 
The  industry  was  ultimately  suppressed,  and  a  large  quantity  of  the  product 
burned. 

*  In  1888  Wen  da  and  Wiorogorski  found  in  the  teas  sold  in  Warsaw 
various  foreign  leaves,  which  they  identified  by  their  anatomical  characters. 


FOREIGN   LEAVES  IN  TEA.  523 

leaves  in  tea,  chemistry  cannot  be  expected  to  play  a  very  active 
part,  though  it  sometimes  affords  very  useful  indications.  Thus 
A.  Wynter  Blyth  has  pointed  out  {Analijst,  ii.  39)  that  a 
crystalline  sublimate  (which  he  believes  to  be  theine)  is  obtainable 
from  a  single  leaf  of  tea.  For  this  purpose  he  boils  the  leaf  for  a 
minute  in  a  watch-glass  with  a  very  little  water,  adds  an  equal  bulk 
of  calcined  magnesia,  and  evaporates  the  mixture  rapidly  to  a  large  drop, 
which  is  transferred  to  a  microscopic  covering  glass  and  evaporated 
nearly  to  dryness  on  a  heated  iron  plate.  It  is  then  covered  by  a 
ring  of  glass,  and  when  the  moisture  is  nearly  diiven  olf  a  second 
slip  of  glass  is  added  as  a  cover.  At  a  somewhat  higher  tempera- 
ture theine  volatilises,  and  on  examining  the  deposit  on  the 
covering  under  the  microscope  may  be  recognised  by  its  character- 
istic appearance.  Other  leaves  than  tea  may  give  a  crystalline 
sublimate,  but  if  no  sublimate  is  obtained  the  leaf  cannot  be  a 
product  of  the  tea-plant. 

A.  W.  Blyth  has  also  proposed  to  utilise  the  constant  presence 
of  manganese  in  tea-leaves  as  a  means  of  recognising  them.  If  a 
single  tea-leaf  be  ignited  in  platinum,  and  the  ash  taken  up  in  a 
bead  of  sodium  carbonate  contained  in  a  loop  of  platinum  wire,  on 
remelting  the  flux  after  a  minute  addition  of  nitre  the  green  colour 
of  the  sodium  manganate  will  be  distinctly  recognisable.  Or  a 
minute  quantity  of  nitre  and  carbonate  of  sodium  can  be  at  once 
added  to  the  ash  on  the  platinum  foil,  when  on  fusing  the  mixture 
a  distinct  green  colour  will  be  obtained  if  manganese  be  present. 

The  author  has  found  manganese  in  the  leaves  of  Camellia  Thea 
(tea),  Camellia  Japonica,  Camellia  sasaTiqua,  Coffea  Aralica,  beech, 
blackberry,  and  sycamore.  Manganese  was  absent  from  the  leaves 
of  the  hawthorn,  ash,  raspberry,  cherry,  plum,  and  rose ;  and  only 
faint  traces  were  detected  in  the  leaves  of  the  Rex  Paraguayensis, 
elm,  birch,  lime,  sloe,  elder,  willow-herb,  and  willow. 

For  the  detection  and  identification  of  foreign  leaves  in  tea,  the 
botanical  and  microscopical  characters  are  best  fitted.  Some  of 
the  sample   to  be  examined  should  be  put  into  hot  water,   and 

Among  the  leaves  recognised  were  those  of  Epilobittm  angiistifolium,  or  French 
willow-herb,  which  formed  the  great  part  of  the  "tea"  sold  in  certain 
localities.  They  also  found  the  leaves  of  Epilohium  hirsutum  (great  willow- 
herb),  Ubnus  campestris  (elm),  Prunus  spinosa  (sloe),  Fragaria  vesca  (straw- 
berry), Fraxinus  excelsior  (ash),  Sambucus  nigra  (elder),  Rosa  canina  (dog- 
rose),  and  Ribes  nigrum  (black  currant).  The  infusion  of  willow-herb  is  darker 
than  that  of  tea,  and  gives  a  precipitate  of  mucilage  on  treatment  with  alcohol. 
An  article  known  in  Russia  as  "Karpar  tea"  also  contains  an  admixture 
of  the  leaves  of  Epilobium  angustifolium.  Two  samples  examined  by  J, 
Nikitinsky  in  1885  yielded  7*87  and  10*43  per  cent,  of  ash,  six  repre- 
sentative genuine  teas  yielding  from  5 '60  to  6 '87  per  cent. 


524  CHARACTERS  OF  TEA  LEAVES. 

when  the  leaves  have  unfolded  they  are  spread  out  on  a  glass 
plate  and  held  up  to  the  light,  when,  with  the  aid  of  a  lens,  the 
venation,  serration,  &c.,  can  be  readily  observed.  A  valuable  aid 
to  the  examination  consists  in  treating  the  leaves  with  a  solution 
of  sodium  hypobromite,  or,  as  suggested  by  A.  Wynter  BlyLh,  a 
strongly  alkaline  solution  of  potassium  permanganate.  In  using 
the  reagent,  the  leaf  should  be  enclosed  between  two  microscopic 
cover-glasses,  a  weight  being  placed  on  the  upper  one  to  keep  it 
in  position.  On  heating  the  leaf  with  the  reagent,  action  at  once 
commences,  the  colouring  matter  being  first  attacked  and  sub- 
sequently the  cell-membranes.  When  the  action  is  sufficiently 
advanced,  the  leaf  is  removed,  washed,  and  immersed  in  hydro- 
chloric acid,  which  leaves  the  leaf  as  a  translucent  white  membrane 
in  which  the  details  of  structure  can  be  readily  observed.  J.  Bell 
removes  the  skin  of  the  leaf  by  immersing  it  in  "  water  containing 
a  few  drops  of  nitric  acid,"  and  gradually  heating  to  the  boiling- 
point,  when  the  skin  rises  in  blisters,  and  may  be  readily  removed 
by  a  camel's-hair  brush. 

The  primary  venation  of  the  tea-leaf  consists  of  a  series  of  well- 
defined  loops,  which  are  not  met  with  in  most  leaves  likely  to  Ije 
used  as  adulterants.  The  serrations  are  not  mere  saw-teeth  on  the 
margin  of  the  leaf,  but  actual  hooks.^  The  serration  stops  short 
abruptly  at  some  distance  from  the  base.  The  Assam  tea-loaf  is 
sometimes  biserrate.  At  the  apex  of  the  tea-leaf  there  is  a  distinct 
notch,  instead  of  a  point.  The  epidermis  of  the  under-surface  is 
seen  under  the  microscope  to  consist  of  distinct  sinuous  cells,  with 
numerous  oval  stomata,  and  a  few,  long  unicellular  hairs.^  On  the 
upper  surface  the  stomata  are  less  numerous.  If  tlie  under  surface 
of  the  tea-leaf  be  examined  under  the  microscope  after  separation  of 
the  cuticle,  the  peculiar  and  characteristic  space  between  the  twin 
cells  of  the  stomata  may  be  readily  perceived. 

T.  Taylor  has  pointed  out  the  presence  of  "stone  cells  "in 
the  leaves  of  tea  and  Camellia  Japonica^  and  confirms  the  observa- 
tions of  Blyth  as  to  the  absence  of  these  formations  in  the  leaves 
of  the  willow,  sloe,  beech,  ash,  black-currant,  raspberry,  and  Ilex 
Paraguay ensis.  Taylor  prepares  the  leaves  for  examination  by 
boiling  them  in  a  strong  solution  of  caustic  potash  or  soda. 

^  The  serrations  are  verj-  strongly  marked  on  mature  leaves,  but  are  indis- 
tinct or  almost  wanting  in  the  delicate  leaf-buds  which  constitute  "flowery 
pekoe." 

^  Tea-hairs  are  conical,  pointed,  slightly  bent  towards  the  base.  They  have 
very  thick  walls,  and  the  central  duct  usually  contains  granular  matter. 
Numerous  hairs  are  observable  ou  young  tea-leaves,  but  on  old  leaves  they  are 
boiuetimes  wholly  wanting. 


FOREIGN   LEAVES  IN  TEA.  525 

In  the  leaf  of  the  blackthorn  or  sloe  {Prunus  communis 
or  P.  spinosay  the  serratures  are  direct  incisions,  numerous,  often 
irregular,  and  extending  to  the  base.  There  are  no  spines.  The 
cells  of  the  epidermis  are  not  sinuous,  and  are  much  smaller  than 
those  of  tea,  especially  on  the  under  surface.  The  cells  on  the 
upper  surface  are  striated.  The  stomata  of  the  sloe-leaf  are  smaller 
and  less  numerous  than  those  of  tea.  The  hairs  are  shorter  and 
coarser  than  those  of  the  tea-leaf ;  are  marked  in  a  peculiar  manner, 
and  have  a  club-shaped  enlargement  at  the  base. 

The  leaf  of  the  elder  (Sambucus  nigra)  is  more  pointed  than 
that  of  the  tea-plant,  and  the  lobes  are  unequal  at  the  base.  The 
serrations  are  direct  incisions.  The  midriff  has  hairs  on  it,  and  on 
the  leaf  itself  there  are  two  distinct  kinds  of  hairs — one,  a  short, 
spinous  hair,  and  the  other  jointed  and  club-like. 

In  the  leaf  of  the  willow  (Salix  alba)  the  serrations 
much  resemble  those  of  tea,  but  the  cells  of  both  the  upper  and 
under  epidermis  are  much  smaller  than  in  tea,  and  the  walls  are 
not  sinuous.  The  hairs,  which  are  very  abundant  on  both  sides  of 
the  leaf,  are  long,  unicellular,  and  sinuous.  The  elongated  form  of 
the  willow-leaf  and  the  character  of  the  venation  also  distinguish 
it  from  tea. 

The  appearance  of  the  leaf  of  the  hawthorn  (Cratcegus 
monogyna  and  C.  oxyacantha)  is  well  known.  The  cells  of  the 
epidermis  are  mostly  quadrilateral,  with  very  sinuous  outlines, 
especially  on  the  under  surface.  The  stomata  are  oval  or  nearly 
round,  large,  and  numerous. 

The  leaves  of  the  beech  {Fagus  sylvatica)  are  ovate,  obscurely 
dentate,  with  parallel  venations  running  right  to  the  edge. 

The  leaves  of  Qhloranfhus  inconspicum  are  long,  oval,  serrated, 
wrinkled,  with  venations  running  nearly  to  the  edge,  and  there 
by  their  intersection  forming  little  knots  which  give  the  margin 
of  the  leaf  a  very  rough  feeling.  The  cells  of  the  epidermis  are 
very  large,  and  the  stomata  oval  and  rather  numerous. 

The  leaves  of  Camellia  sasanqua  are  oval,  only  obscurely  serrate 
if  at  all,  and  of  a  tough  leathery  texture.  The  lateral  veins  are 
inconspicuous.  Both  the  upper  and  lower  epidermis  show  a 
peculiar  dotted  or  reticulated  structure,  and  the  lower  is  studded 
with  numerous  small  oblong  stomata. 

The  leaves  of  Lithosj)ermum  officinale  (the  common  gromwell) 
have  been  extensively  used  in  Bohemia  for  adulterating  tea.     They 

^  A  specimen  of  sloe-leaves  gathered  early  in  September  gave,  after  drying, 
the  following  results  (in  the  author's  laboratory): — Moisture,  6*40  j)Hrcent. ; 
insoluble  matter  (on  whole  leaves),  55*90  ;  tannin  (by  gelatin),  16'00  ;  gum, 
&c.,  8*90  ;  total  ash,  8*74  ;  and  ash  soluble  in  water,  4*70  per  cent. 


526  .     ILEX.  PARAGUAYENSIS. 

are  lanceolate,  with  a  hairy  under-surface,  are  destitute  of  alka- 
loid and  essential  oil,  contain  about  9  per  cent,  of  fat  and  8  of 
tannin,  and  leave  about  20  per  cent,  of  ash  on  ignition  {Jour. 
Chem.  Soc,  xl.  131). 

The  general  appearance  and  venation  of  tea,  and  leaves  which 
have  been,  or  may  possibly  be,  employed  for  its  adulteration,  are 
shown  by  two  plates  at  the  end  of  the  volume  (page  572).  The 
illustrations  are  life-size  reproductions,  by  the  collotype  process,  of 
photographs  of  leaves,  taken  by  J.  T.  S  t  e  v  e  n  s  o  n  in  the  author's 
laboratory. 

A.  Wy  nter  Blyth  has  pointed  out  the  characteristic  appear- 
ance of  the  "skeleton-ash"  left  on  igniting  leaves  from 
different  sources.  The  leaf  to  be  examined  is  placed  between  two 
circles  of  microscopic  cover-glass,  the  upper  one  weighted  with  a 
silver  coin,  and  the  whole  ignited  cautiously  in  a  flat  platinum  dish, 
or  on  platinum  foil.  Before  the  carbon  is  completely  consumed 
the  heat  is  discontinued,  and  the  skeleton-ash  examined  under  the 
microscope. 

Mate.    Paraguay  Tea. 

Mate^  orYerba  consists  of  the  prepared  twigs  and  leaves  of 
Ilex  Paraguayensis,  or  Brazilian  holly.^ 

Byasson  found  in  caa-guacu,  the  commonest  kind  of  mate, 
consisting  of  the  large  and  old  leaves  with  twigs  and  fragments  of 
wood: — Caffeine,  1*85  per  cent.;  a  substance  resembling  bird- 
lime, fatty  and  colouring  matters,  3 "87  ;  complex  glucoside,  2*38  ; 
resin,  0*63  ;  mineral  matter,  3*92  ;  and  an  undetermined  propoi>- 
tion  of  malic  acid. 

Some  fresh  leaves  of  Bex  Paraguayensis,  grown  in  Cambridge 
Botanical  Gardens,  were  found  in  the  author's  laboratory  to  contain 
69*1  per  cent,  of  water.  An  analysis  of  the  same  leaves  after 
drying  at  100°  C.  showed: — Insoluble  matter,  57*94  (  =  hot-water 
extract,  42-06);  tannin  by  PbAg,  15*62;  tannin  by  CuAg, 
15"66;  caffeine,  1"13;  total  ash,  6*14;  soluble  ash,  3'56  ;  alka- 
linity of  soluble  ash  (as  KgO),  0"12  per  cent. 

A.  W.  Hofmann  found  in  mate  0'3  per  cent,  of  caffeine  and  a 
variety  of  tannin  identical  in  every  respect  with  that  present  in  tea. 

^  The  word  mate  is  not  accented,  as  sometimes  written,  but  it  should  be 
pronounced  as  two  syllables. 

2  Various  allied  species  are  recognised,  but  Ilex  Paraguayensis  appears  to 
be  the  only  one  cultivated.  It  has  been  grown  in  Spain,  Portugal,  and  Cape 
Colony,  in  addition  to  its  native  habitat.  At  the  present  time  it  is  used  by 
about  12,000,000  of  peo})le,  the  annual  consumption  in  the  Argentine  Republic 
alone  being  twenty-seven  million  pounds. 


TEA   SUBSTITUTES.  527 

P.  JSr.  Arata  found  the  tannin  of  mate  to  be  analogous  to  but  not 
identical  with  that  of  coffee.  On  dry  distillation  he  found  it  to  yield 
resorcinol  as  well  as  catechol.  Caffetannic  acid  he  regards  as  dioxy- 
paracinnamylic  acid,  and  matetannic  acid  as  belonging  to  the  group 
of  oxyphenylpropionic  acid.  Soubeiran  and  Delondre 
state  that  mate  contains  the  same  essential  constituents  as  the 
coffee-leaf,  and  in  greater  proportion  than  the  coffee-seeds.  This 
conclusion  is  confirmed  by  Theodore  Peckolt  in  a  valuable 
resume  of  the  subject  {Pharm.  Jour.,  [3],  xiv.  121),  including 
some  elaborate  proximate  analyses  of  mate. 

The  aromatic  principle  of  mate  has  not  been  isolated,  but  by 
dry  distillation  a  volatile  oil  of  phenolic  character  is  obtained. 

The  ash  of  mate  resembles  that  of  tea  in  containing  a  notable 
proportion  of  manganese. 

The  leaves  of  the  Y  o  p  o  n  {Ilex  cassine)^  a  shrub  or  small  tree 
growing  on  the  coast  of  Virginia  and  Carolina,  have  been  used  as  a 
beverage.^  F.  P.  Yen  able  (Chem.  News,  lii.  172)  found  in 
an  air-dried  sample: — Moisture,  13'19;  water  extract,  26*55; 
tannin,  7*39  ;  caffeine,  0  27;  and  ash,  6 '7 5  per  cent.  The  ash 
contained  manganese. 

Coffee.^ 

Commercial  coffee  consists  of  the  seeds  of  Coffea  Arabica  and 
allied  species  belonging  to  the  order  Ginclionacece.^  The  coffee- 
tree  is  a  shrub-like  plant  cultivated  in  various  tropical  countries. 
The  best  coffee  that  reaches  England  comes  from  India,  Java,  and 
Ceylon.      A  little  "Mocha"  coffee  comes  from  Arabia,  but  the 

1  Although  the  leaves  of  tea,  coffee,  and  Brazilian  holly  are  almost  the  only 
ones  known  to  contain  caffeine,  a  beverage  is  prepared  from  the  leaves  of  many 
other  plants  in  various  parts  of  the  world.  Thus,  Catha  edulis,  a  shrub 
related  to  the  spindle  tree,  is  extensively  cnltivated  in  the  interior  of  Arabia,  and 
the  leaves,  known  as  K  h  a  t,  C  a  ft  a  or  Arabian  tea,  are  used  both  as  a  beverage 
and  for  chewing.  Fahuin,  or  orchid  tea,  is  made  from  the  leaves  of 
Angrcecumfragram,  growing  in  the  Mauritius,  and  some  years  since  was  intro- 
duced into  Paris  as  a  regular  article  of  commerce.  Th^  Arab  e,  a  substitute 
for  tea  which  has  been  sold  in  Paris,  consists  of  the  small  leaves  of  Paronychia 
argentea,  a  plant  growing  on  the  slopes  of  the  Atlas  Mountains.  Batoum 
or  Trebizonde  tea  is  made  from  the  leaves  of  Vaccinium  ardostaphylos, 
a  plant  closely  allied  to  the  cranberry.  Cape  tea  and  Bush  tea  are 
described  in  the  footnote  on  page  503.    Karper  tea  is  described  on  page  523. 

2  French ;  le  CafL     German ;  der  Kaffee. 

3  Three  species  oi  Coffea,  distinct  from  each  other,  are  now  grown  : 1.  The 

Arabian  or  Mocha  coffee-plant  has  short  upright  branches,  with  a  brittle  leaf 
and  seeds  usually  single  in  the  berries.  2.  The  Jamaica  coffee-plant  bears 
longer  and  more  pliable  branches  than  the  Arabian,  has  a  tougher  leaf,  and 
the  seeds  are  almost  always  double  in  the  berries.     3.  The  East  Indian  or 


528  COMPOSITION  OF   RAW   COFFEE. 

greater  part  from  India.  Brazil  at  the  present  time  furnishes 
about  one-half  of  the  world's  supply  of  coffee.^ 

Commaille  {Monit  Scient,  [3],  vi.  779)  gives  the  following 
as  the  chemical  composition  of  undressed  Mysore  coffee  : — Moisture 
(from  24  samples),  6*3  to  15-7  per  cent.;  fatty  matters,  12-68; 
glucose,  260;  legumin-casein,  1*52;  albumin,  1'04;  caffeine,  0'42 
to  1*31 ;  and  ash,  3*88  per  cent. 

0.  Levesie  (Arch.  Pharm.,  [5],  iv.  294;  Jour.  Chem.  Soc.y 
xxxi.  752)  obtained  the  following  range  of  figures  by  the  analysis 
of  seven  typical  samples  of  raw  coffee  ; — 


Caffeine, 

Gummy  matter, 

Fat,      . 

Tannic  and  caffetannic  acids, 

Cellulose, 

Ash,     . 


0*64  to    1-53  per  cent. 


20-6    „  27-4 
14-76  „  21-79 
19-5    ,,  23  1 
29-9    „  36-4 
3-8    „    4-9 


It 


J.  Bell  (Analysis  and  Adulteration  of  Foods,  i.  43)  gives 
the  following  analyses  of  typical  samples  of  raw  and  roasted 
coffee  : — 

Bengal  plant  has  smaller  leaves  than  the  Jamaica  coffee,  and  very  small 
berries.  The  Liberian  coffee-plant  {Coffea  Liberiea)  appears  to  be  a  distinct 
species,  which  is  little  subject  to  disease,  and  has  been  successfull)'  introduced 
into  the  East  Indies. 

The  coffee  fruit  usually,  but  not  always  (see  above),  contains  two  twin  seeds, 
which  touch  each  other  on  the  flattened  surface.  These  are  contained  in  a 
pulp  which  is  removed  by  water  and  a  process  of  fermentation  ;  and  the 
membranous  pericarp  (technically  termed  "parchment")  which  incloses  each 
seed  is  removed  by  rollers  and  winnowing. 

The  parchment  from  coffee-berries  is  imported  to  England  in  considerable 
quantities,  and,  when  roasted,  is  said  to  form  an  ingredient  of  the  beverage 
sold  in  cheap  coffee-shops. 

An  analysis  of  unroasted  "parchment,"  made  in  the  author's  laboratory 
by  C.  M.  Gaines,  showed  it  to  contain  : — Water,  9*43  ;  essential  oil,  0  068  ; 
caffeine,  0*27  ;  hot-water  extract,  I'Gl  ;  total  ash,  10-41  ;  and  soluble  ash, 
0*19  per  cent.     A  somewhat  coffee-like  aroma  was  developed  by  roasting. 

It  is  stated  that  the  Arabs  in  the  neighbourhood  of  Jedda  discard  the  kernel 
of  the  coffee-berries  and  make  an  infusion  of  the  husks  {Pharm.  Jour.,  [3], 
xvii.  656). 

^  In  Australia,  an  infusion  of  slightly  roasted  coffee-leaves  is  drunk  in  the 
same  manner  as  tea.  Its  taste  suggests  at  once  that  of  tea  and  tobacco.  The 
leaves,  when  burnt  or  roasted,  exhale  a  powerful  odour  of  tobacco,  and  the 
smell  of  the  condensed  vapours  strongly  suggests  that  of  tobacco -juice. 
0.  Hehner,  who  has  analysed  the  leaves  {Analyst,  iv.  84),  found  only  0*29 
per  cent,  of  caffeine. 


COMPOSITION  OF  COFFEE. 


62i) 


Mocha  Coffee. 

East  Indian  Coflfee. 

Raw. 

Roasted. 

Raw. 

... 
Roasted. 

Moisture 

Caffeine, 

Saccharine  matter, 

Caffeic  acids 

Alcoholic      extract,     containing ) 
nitrogenous     and     colouring  [• 
matter,        .        .        .        .        ; 

Fat  and  oil, 

Legumin  and  albumin,   . 

Dextrin, 

Cellulose  and  insoluble  colouring") 
matter,        .        .        .        .       / 

Ash, 

8-98 
1-08 
9-55 
8-46 

6-90 

12-60 
9-87 

•87 

37-95 
3-74 

0-63 

•82 

•43 

4-74 

14-14 

13-59 
11^23 

1-24 

48-62 
4-56 

9-64 
1-11 
8-90 
9-58 

4-31 

11-81 
11-23 

-84 

38-60 
3-98 

1-13 

105 

•41 

4-52 

12-67 

13-41 
13  13 
1-38 

47-42 

4-88 

100-00 

100  00 

100-00 

100-00 

Bell  believes  the  sugar  of  coffee  to  be  a  peculiar  species,  possibly- 
allied  to  melezitose.  G.  L.  Spencer,  on  the  other  hand,  has 
definitely  proved  that  the  carbohydrates  of  coffee  consist  very 
largely  of  sucrose,  which  he  has  isolated  in  considerable  quan- 
tities. There  is  likewise  present  a  body  which  yields  galactose 
on  hydrolysis,  as  also  a  pentose-yielding  gum. 

Caffetannic  Acid,  CigHigOg,  called  by  Payen  chlorogenic 
acid,  exists  in  coffee-berries  in  the  proportion  of  3  to  5  per  cent., 
probably  as  a  calcium  or  magnesium  salt,  or,  according  to  Payen, 
as  a  double  caffetannate  of  potassium  and  caffeine.  It  is  prepared 
by  diluting  an  alcoholic  infusion  of  coffee  with  water,  filtering  from 
precipitated  fatty  matter,  and  precipitating  the  boiling  filtrate  with 
lead  acetate.^  On  decomposing  the  washed  precipitate  with 
sulphuretted  hydrogen  free  caffetannic  acid  is  obtained.  It  forms 
a  yellowish-white  powder,  or   groups  of   colourless  mammillated 


^  W.  H.  K  r  u  g  determines  caffetannic  acid  as  a  lead  salt  He  treats  2 
grammes  of  coffee  with  10  c.c.  of  water,  and  digests  for  36  hours,  then  adds 
25  c.c.  of  rectified  spirit,  and  digests  24  hours  more.  The  liquid  is  filtered, 
the  residue  washed  with  rectified  spirit,  and  the  filtrate  heated  to  the  boiling- 
point.  A  boiling  concentrated  solution  of  lead  acetate  is  added,  which  throws 
down  a  precipitate  of  Pb3(Ci5Hi508)2.  When  this  has  become  flocculent  it  is 
filtered  off,  washed  with  alcohol  till  the  washings  are  free  from  lead,  washed 
with  ether  to  remove  traces  of  fat,  dried  at  100°,  and  weighed. 

VOL.  III.  PART  II.  2   L 


530  CAFFETANNIC   ACID. 

crystals.  It  is  very  soluble  in  water,  less  soluble  in  alcohol,  and 
only  very  sparingly  in  ether.  Caffetannic  acid  has  an  astringent 
taste,  and  the  solution  strongly  reddens  litmus.  It  gives  a  dark 
green  coloration  with  ferric  chloride,  and  precipitates  the  sulphates 
of  quinine  and  cinchonine  ;  but  not  gelatin,  ferrous  salts  or  tartar- 
emetic.  It  reduces  silver  nitrate  on  heating,  forming  a  metallic 
mirror.     The  salts  turn  green  in  the  air. 

On  dissolving  caffetannic  acid  in  caustic  alkali  or  ammonia,  and 
exposing  the  solution  to  the  air,  the  liquid  acquires  a  bluish-green 
colour  owing  to  the  formation  of  the  oxidation-product,  v  i  r  i  d  i  c 
acid,  which  is  an  amorphous  brown  substance,  very  soluble  in 
water  to  form  a  solution  which  is  turned  green  by  alkalies.  It 
gives  a  bluish-green  precipitate  with  baryta-water,  and  a  blue  with 
lead  acetate.  Viridic  acid  dissolves  in  concentrated  sulphuric  acid 
to  form  a  crimson  solution,  which  on  dilution  with  water  gives  a 
flocculent  blue  precipitate. 

On  prolonged  boiling  with  caustic  alkalies,  caffetannic  acid  is 
split  up  into  a  sugar  and  caffeic  acid,  CgHgO^,  which 
crystallises  from  the  neutralised  liquid  and  has  the  constitution 
of  a  dihydroxy-cinnamic  acid.  By  fusion  with  caustic  potash, 
caffetannic  acid  yields  protocatechuic  and  acetic  acids.  Heated 
alone  it  gives  catechol. 

Roasting  of  Coffee.  During  the  process  of  roasting,  the 
aroma  of  coffee  is  developed  and  the  toughness  of  the  beans 
destroyed,  so  that  subsequent  grinding  is  facilitated.  If  the  roast- 
ing be  insufficient,  the  rawness  is  not  destroyed  and  the  flavour 
not  fully  developed;  while  if  over-roasted,  the  product  has  a 
nauseous  empyreumatic  flavour. 

When  roasted  to  a  yellowish -brown,  coffee  loses,  according  to 
Cadet,  about  12 J  per  cent,  of  its  weight,  and  in  this  state  is 
difficult  to  grind.  When  roasted  to  a  chestnut-brown  it  loses  18 
per  cent.,  and  when  it  becomes  entirely  black,  though  not  all 
carbonised,  it  has  lost  23  per  cent.  In  practice,  the  loss  of  weight 
in  roasting  coffee  is  between  12  and  20  per  cent,  (of  which  about 
8  per  cent,  represents  water  removable  at  100°  C),  and  if  the 
latter  figure  is  reached,  the  product  is  injured.  According  to 
Watson  Will,  the  usual  yield  of  roasted  coffee  is  about  98  lbs. 
from  1  cwt.  of  raw  berries.  This  corresponds  to  a  loss  of  12*5  per 
cent. 

K  o  n  i  g  found  that  on  roasting  coffee-berries  to  a  light  browR 
the  total  loss  of  weight  was  1777  per  cent.,  of  which  8*66  was 
water  and  9'11  per  cent,  organic  matter.  The  original  coffee  con- 
tained 11*19  per  cent,  of  moisture,  and  after  roasting,  still  retained 
3*19  per  cent.     Eliminating  this  extraneous  water  from  the  results. 


ROASTING   OF   COFFEE. 


531 


the  percentage  composition  of  the  raw  and   roasted  coffee  was  as 
follows : — 


Raw. 

Roasted. 

Caffeine, 

1-33  per  cent. 

1-42  per  cent. 

Fat, 

14-91       „ 

16-14 

Albuminous  matters,       .... 

11-43        „ 

12-31 

Sugar, 

3-66        „ 

1-35        „ 

Undefined  non-nitrogenous  matters, 

34-55        „ 

39-84        „ 

Cellulose, 

31-24        „ 

25-07        „ 

Ash 

3-92        „ 

3-87        „ 

101-04  (!)  per  cent. 

100-00  per  cent. 

Total  matters  soluble  in  water,     . 

30-93  per  cent 

28'36  per  cent. 

According  to  Paul  and  C  o  w  n  1  e  y  {Pliarm.  Jour.,  [3],  xvii. 
655,  821)  there  is  no  appreciable  loss  by  volatilisation  of  caffeine 
during  the  roasting  of  coffee,  unless  the  process  is  carried  to  excess. 
But  Paul  admits  that  the  water  condensed  in  the  place  leading  from 
the  roasting  often  contains  some  caffeine,  which  he  considers  has 
been  probably  carried  over  mechanically  (Pharm.  Jour.,  [3],  xvii. 
821).  Watson  Will  (ibid.,  page  684)  states  that  he  has 
never  failed  to  find  caffeine  in  the  sublimate  obtained  in  coffee- 
roasting. 

The  chemistry  of  the  roasting  of  coffee  has  been  studied  by  0. 
Bernheimer  {Monatsh.  Chem.,  i.  456 ;  Jou7\  Chem.  Soc,  xlii. 
230),  who  roasted  coflee  till  it  had  lost  about  25  per  cent,  of  its 
weight.^     The  uncondensible  vapours  consisted  chiefly  of  carbon 

1  Paul  points  out  that  the  caffeine  exists  in  coffee  in  the  form  of  cafFetannate, 
which  compound  will  not  suffer  decomposition  at  the  ordinary  temperature  of 
roasting.  Considering  the  great  facility  with  which  salts  of  caffeine  undergo 
decomposition,  this  statement  seems  to  require  confirmation. 

2  Fifty-  kilogrammes  of  coffee  yielded  5  litres  of  aqueous  distillate  and  680 
grammes  of  solid  matter  floating  thereon.  On  agitating  this  with  ether,  fatty 
acids,  quinol  and  caffeol  were  extracted,  while  caffeine,  acetic  acid,  methyl- 
amine  and  trimethylamine  remained  in  the  aqueous  liquid.  On  evaporating 
the  ethereal  solution,  and  fractionally  distilling  the  residual  dark,  coffee-smelling 
oil,  a  few  drops  of  an  acetone-like  liquid  passed  over,  followed  by  a  little  acetic 
acid  and  water.  Between  200°  and  300°  caffeol  distilled,  and  above  that  tem- 
perature palmitic  and  other  solid  fatty  acids.  On  neutralising  these  and  the 
200°-300°  fraction  with  sodium  carbonate,  a  viscid  dark  oil  was  thrown  dowu, 


532  CAFFEOL. 

dioxide,  and  by  passing  them  through  dilute  hydrochloric  acid 
a  resinous  substance  having  the  appearance  of  pyrrol-red  was 
deposited.  Among  the  solid  and  liquid  bodies  volatilised,  Bern- 
heimer  found : — Palmitic  and  other  solid  fatty  acids,  0*48  per 
cent.;  caffeine,  0*28  per  cent.;  caffeol,  0*05  per  cent.;  besides 
water  and  acetic  acid.  Quinol,  pyrrol,  acetone,  methylamine,  and 
trimethylamine  also  occurred  as  secondary  products. 

Caffeol,  CgH^QOg,  is  an  oily  liquid  smelling  very  strongly  of 
coffee,  and  no  doubt  is  the  substance  to  which  the  aroma  of 
roasted  coffee  is  due.  It  may  be  obtained  by  distilling  roasted 
and  powdered  coffee  with  water,  shaking  the  distillate  with  ether, 
and  evaporating. 

Caffeol  boils  at  196°,  and  is  not  solidified  by  a  freezing  mixture. 
It  is  not  sensibly  soluble  in  cold  water,  to  which,  however,  it  im- 
parts its  characteristic  odour.  It  is  slightly  soluble  in  hot  water, 
very  slightly  in  aqueous  potash,  and  with  great  facility  in  alcohol 
and  ether.  The  alcoholic  solution  gives  with  ferric  chloride  a  red 
coloration,  said  not  to  be  destroyed  on  adding  sodium  carbonate. 
By  fusion  with  caustic  potash,  caffeol  yields  saHcylic  acid,  and, 
according  to  Botsch  (Monatsh.  Chem.,  ii.  621;  Jour.  Chem. 
Soc,  xlii.  174),  is  isomeric  with  methyl-salicyl  alcohol,  tlie  two 
compounds  having  the  following  constitution  : — 

CeH4(O.CH3).CH20H  C6H,(OH).CH2.0CH3 

Methyl-salicyl  alcohol.  Caffeol. 

Paul  and  Cownley  {Pharm.  Jour.,  [3],  xvii.  822)  found 
that  on  infusing  coffee  in  six  times  its  weight  of  boiling  water, 
about  88  per  cent,  of  the  caffeine  passed  into  solution.  Three  fluid 
ounces  of  such  an  infusion  contained  2*36  grains  of  caffeine.  As 
the  medicinal  dose  of  caffeine  is  from  1  to  5  grains,  a  cup  of  coffee 
may  be  expected  to  have  a  marked  effect  as  a  stimulant. 

The  dietetic  value  of  coffee  is  possibly  dependent  as  much  upon 
the  presence  of  caffeol  as  on  that  of  caffeine.  According  to  M. 
P  a  r  g  a  s,  the  effect  of  caffeol  on  the  heart's  action  is  the  opposite 
to  that  of  caffeine,  and  increases  the  strength  and  rapidity  of  the 
pulsations. 

According  to  C  o  u  t  y,  G  u  i  m  a  r  a  e  s,  and  N  i  o  b  e  y  (Compt. 
Bend.,  xcix.  85)  coffee  diminishes  the  activity  of  the  simple  com- 
bustions which  produce  carbon  dioxide,  but  increases  the  forma- 

which  was  separated  from  the  aqueous  solution  of  soap  and  washed  with  water 
containing  a  little  caustic  alkali.  This  dissolved  out  quinol,  which  was  isolated 
by  acidulating  the  washings  and  extracting  with  ether.  The  viscid  oil,  con- 
sisting of  impure  catfeol,  was  dried  by  calcium  chloride  and  fractionally  dis- 
tilled, when  the  greater  part  passed  over  between  195°  and  197°. 


PHYSIOLOGICAL  EFFECTS  OF  COFFEE. 


533 


tion  and  excretion  of  urea,  and  the  assimilation  of  meat  and  other 
nitrogenous  foods.  It  is  a  complex  aliment  which  renders  the 
organism  capable  of  consuming  and  destroying  larger  quantities  of 
nitrogenous  substances,  and  hence  may  be  regarded  as  an  indirect 
source  of  available  energy. 

Commercial  coffee  is  subject  to  a  variety  of  sophistications,  both 
in  the  form  of  berry  and  after  grinding.  So  far  as  the  United 
Kingdom  is  concerned,  the  majority  of  the  frauds  formerly  practised 
are  obsolete,  or  nearly  so,  but  certain  illicit  practices  subsist. 

Coffee-berries  vary  considerably  in  size  and  character  accord- 
ing to  their  origin.^  The  following  table  shows  the  number  of 
seeds  required  to  fill  a  50  c.c.  measure  (Thorpe's  Diet.  Applied 
Chem.,  ii.  578) :— 


Fine  brown  Java, 

187 

Good  ordinary  Java,  . 

223 

Fine  Mysore,      . 

198 

Fine  Ceylon  plantation,      . 

225 

Fine  Neilgherry, 

203 

Good  average  Rio, 

236 

Costa  Rica, 

203 

Medium     Ceylon     planta- 

Good ordinary  Guatemala, 

207 

tion 

238 

Good  La  Guayro, 

210 

Manilla,     .... 

248 

Good  average  Santas, 

213 

Ordinary  Mocha, 

270 

Fine  long-berry  Moo-ha, 

217 

West  African,    . 

313 

According  to  L.  Pad^  (Bull.  Soc.  Ghim.,  xlvii.  501),  raw  coffee 
which  has  been  damaged  by  sea-water  is  sometimes  washed,  de- 
colorised with  lime-water,  again  washed,  dried  rapidly,  and  coloured 
either  by  slight  roasting  or  by  dyeing  with  azo-oranges.  By 
such  manipulations,  green  Santas  coffees  are  said  to  be  increased 
25  per  cent,  in  value,  and  made  to  pass  for  Java  growths.  E. 
"Waller  states  that  South  American  coffees  are  often  exposed 
to  a  high  moist  heat,  which  changes  their  colour  from  green  to 
brown,  in  imitation  of  Java  coffee.  He  found  coffee-berries  coloured 
with  Scheele's  green,  yellow  ochre,  chrome-yellow,  burnt  umber, 

^West  Indian  coffee-berries  are  regular  in  size,  pale  yellowish,  firm  and 
heavy,  with  a  fine  aroma,  and  they  lose  comparatively  little  on  roasting. 
Brazilian  coffee  is  larger,  less  solid,  greenish  or  white,  and  usually  classed 
as  ' '  low  "or  "  low  middling. "  Javanese  coffee-berries  are  smaller,  slightly 
elongated,  light,  and  deficient  in  aroma  and  essential  oil.  When  new,  Java 
coffee  is  pale  yellow,  and  of  less  value  than  when  old  and  brown.  The  deeper 
colour  is  due  to  curing  as  well  as  age.  It  has  been  artificially  coloured. 
Ceylon  produces  all  descriptions  of  coffee,  but  the  ordinary  plantation 
coffees  are  even-coloured,  slightly  canoe-shaped,  strong  in  aroma  and  flavour, 
heavy,  and  more  susceptible  of  adulteration  than  the  other  kinds.  Genuine 
Mocha  coffee  is  small  and  dark  yellow  in  colour,  and  considered  of  the 
highest  quality. 


534  COFFEE-BERRIES. 

Venetian  red,  &c.  When  possible,  such  facings  should  be 
detached  by  agitating  the  berries  with  cold  water  and  examining 
the  sediment.  Organic  colouring  matters  can  be  detected  by- 
soaking  the  berries  in  alcohol,  which  is  not  coloured  by  genuine 
coffee.  On  evaporating  the  alcoholic  solution  to  dryness,  and  taking 
up  the  residue  in  water,  a  solution  will  be  obtained  which  will  give 
the  characteristic  reactions  of  the  coal-tar  dyes. 

The  specific  gravity  of  twenty-four  samples  of  genuine  raw 
coffee-berries  was  found  by  Pad^  to  range  from  1"368  to  1041, 
while  the  density  of  the  same  samples,  after  roasting  in  the  ordinary 
manner,  varied  from  0*635  to  0"500.  Raw  coffee  which  is  lighter 
than  water  may  be  suspected  of  having  been  damaged  by  sea- water 
or  other  means,  and  subsequently  washed  and  improved  in  colour 
by  partial  roasting. 

The  specific  gravity  of  coffee-berries  is  ascertained  by  Pad^  by  a 
special  apparatus  described  in  his  paper.  In  the  case  of  unroasted 
coffee,  the  gravity  can  be  readily  observed  by  immersing  a  few  of 
the  berries  in  saturated  brine,  which  is  then  diluted  with  water 
till  the  coffee  remains  suspended  in  the  liquid,  the  specific  gravity 
of  which  is  then  taken.  With  roasted  coffee,  the  brine  must  be 
replaced  by  the  very  lightest  gasolene,  the  density  of  which  can  be 
increased  if  necessary  by  the  gradual  addition  of  ordinary  kerosene. 
Another  plan  of  ascertaining  the  specific  gravity  of  coffee-berries  is 
to  introduce  as  many  as  possible  into  a  tared  50  c.c.  flask  or  other 
vessel  of  known  capacity.  The  weight  is  then  ascertained,  and 
the  flask  filled  to  the  mark  with  mercury.  The  weight  is  again 
observed,  when  the  increase  will  be  the  weight  of  mercury  required 
to  fill  the  interstices  between  the  berries  : — 

Weight  of  berries  in  grammes  x  13;59 ^^  ^^^.^^^^^ 

(Measure  of  vessel  in  c.  c.  x  13-59)  -  weight  of  interstitial 
mercury 

According  to  J.  K  b  n  i  g  (Zeitsch.  angew.  Chem.,  1888,  page  680) 
coffee  is  often  roasted  with  an  addition  of  glucose-syrup,  which 
makes  the  decoction  look  stronger,  and  causes  the  berries  to  hold 
an  additional  7  per  cent,  of  water.^     L.  P  a  d  ^  states  that  roasted 

1  Coffee  so  treated  yields  from  6  to  8  per  cent,  of  soluble  matter  on  agitation 
with  cold  water,  while  coffee  roasted  without  sugar  yields  from  4  to  5  per  cent, 
only.  In  the  former  case,  Fehling's  solution  indicates  from  1  to  1^  per  cent, 
of  reducing  sugar,  against  0"2  to  0'5  in  genuine  coffee.  Stutzer  and 
Reitnair  detect  glucose  by  violently  agitating  20  grammes  of  the  coffee- 
beans  with  500  c.c.  of  water  for  five  minutes.  The  liquid  is  further  diluted 
to  1000  c.c.  and  50  c.c.  of  the  filtered  liquid  evaporated  to  dryness  at  100°. 
The  dry  residue  is  weighed,   ignited,   and  the  ash  deducted.     Pure  roasted 


IMITATION   COFFEE-BERRIES.  535 

coffee-beans  can  be  made  to  take  up  nearly  20  per  cent,  of  water  by 
steaming  them  and  coating  them  with  glycerin,  palm-oil,  or  vaseline 
to  prevent  evaporation.  The  specific  gravity  of  the  berries  is  thereby 
raised  to  0*650-0'770,  and  hence  is  sensibly  above  0*635,  which  is 
the  maximum  figure  for  genuine  roasted  berries. 

YanHamel  Roos  {Revue  Intern,  des  Falsifications,  May  1 5, 
1891)  has  called  attention  to  an  ingenious  method  of  sophisticating 
coffee-berries.  A  sample  examined  by  him  had  the  microscopic 
structure  of  genuine  coffee,  but  showed  an  almost  entire  absence 
of  fat  globules,  and  gave  an  ether-extract  of  less  than  1  per  cent, 
(instead  of  12  to  14).  Roos  suggests  that  the  berries  had  been 
used  for  preparing  coffee-extract,  and  then  re-roasted  with  addition 
of  a  little  sugar. 

As  a  coating  for  coffee,  T.  W.  Moore  has  patented  {Eng.  Pat., 
5033,  1889)  a  mixture  of  milk  or  condensed  milk,  ground  or 
powdered  glue,  "  liquid  glycerin,"  and  refined  lard;  with  the  addition 
in  some  cases  of  bicarbonate  of  soda,  fine  salt,  and  vinegar ! 

Imitation  coffee-berries  were  formerly  manufactured  of  fire-clay. 
These  were  mixed  with  genuine  berries  and  roasted  with  them, 
when  they  absorbed  some  of  the  colouring  matter  and  oil,  and  so 
remained  a  close  imitation.  On  breaking  such  spurious  berries  the 
colour  would  be  seen  to  be  principally  on  the  exterior.  The 
determination  of  the  total  ash  and  silica  would  at  once  lead  to  the 
detection  of  such  a  fraud. 

In  1850,  Messrs  Duckworth  of  Liverpool  took  out  a  patent  for 
moulding  chicory  into  the  form  of  coffee-berries,  and  quite  recently 
several  kinds  of  factitious  coffee-beans  have  been  described. 

A  factory  for  the  manufacture  of  imitation  coffee-berries  on  the 
scale  of  40  to  50  kilogrammes  daily  was  recently  seized  at  Lille  by 
the  French  Government.  It  appeared  in  evidence  that  the  com- 
position of  the  product  was  : — Chicory,  15  kilogrammes;  flour,  35 
kilogrammes  ;  ferrous  sulphate,  J  kilogramme. 

Factitious  coffee-beans  recently  seized  in  Roumania  consisted  of 
coffee-grounds,  chicory,  and  peas. 

In  America  there  are  several  firms  which  extensively  manufacture 
imitation  coffee-beans  and  "  coffee-pellets."  These  preparations 
usually  consist  of  wheat-flour,  chicory,  bran,  and  occasionally 
coffee.  Samples  purchased  and  examined  by  the  chemists  of 
the  U.S.  Department  of  Agriculture  gave  the  following  re- 
sults : — 

coffee  shows  from  0*44  to  0"72  per  cent,  of  soluble  organic  matter,  and  gives  a 
solution  only  faintly  coloured  ;  but  if  roasted  with  sugar  or  glucose  the  organic 
extract  ranges  from  1*81  to  8*18  per  cent.,  and  the  liquid  is  more  or  less 
strongly  coloured. 


536 


FACTITIOUS   COFFEE-BEANS. 


Appearance. 

Specific 
Gravity. 

Composition. 

Roasted  beans,      .    . 
Roasted  beans,      .    . 
Roasted  beans,      .    . 
Roasted  pellets,    .    . 
Roasted  pellets,    .    . 
Roasted  pellets,    .    . 
Raw  beans,  .... 
Roasted  beans,      .    . 
Light-coloured  beans, 
Dark- coloured  beans. 
Roasted  beans,      .    . 
Roasted  granules. 
Roasted  lumps,      .     . 
Roasted  granules,      . 

1-195 
1-198 
1-111 
1-119 
1-183 
1-193 

1-211 
1-174 
1-134 
1-118 

Wheat-flour. 

Wheat-flour,  coffee,  and  chicory. 

' '  Kunst  Kaflee. "  Wheat-flour,  coffee,  and  chicory. 

VWheat-flour,  bran,  and  probably  rye. 

Wheat-flour  and  coffee. 
Wheat-flour. 

1  Wheat-flour  and  probably  sawdust. 

Wheat-flour. 

Hulls  of  peas,  with  molasses. 

Bran  and  molasses. 

Pea  hulls  and  bran. 

A.  W.  Kehnstrom  {Eng,  Pat,  14,970,  1889)  has  described 
a  substitute  for  coffee  prepared  by  boiling  down  whey  or  milk  in  a 
vacuum  to  a  pasty  consistency,  forming  the  product  into  cakes, 
drying  it  below  100°,  cutting  it  into  pieces  the  size  of  coffee-beans, 
and  roasting. 

L.  Jaunnes,  in  1891,  examined  a  factitious  coffee  consisting 
of  acorns  and  cereals. 

An  imitation  coffee  examined  by  J.  K  d  n  i  g  (Zeitsch.  angew. 
Chem.,  1888,  page  680)  closely  resembled  real  coffee  in  appearance, 
but  all  the  berries  were  precisely  the  same  shape.  Under  the 
microscope,  wheat-starch  was  detected,  and  Konig  concluded  that 
the  article  consisted  of  roasted  wheat  dough  of  low  quality. 
E.  Fricke  (Zeitsch.  angew.  Chem.,  1889,  page  310)  has  described 
a  factitious  coffee  containing  caffeine,  and  apparently  made  from 
lupine-seeds  (compare  page  544).  K.  P  o  r  t  M  e  (Chem.  Gentralhl., 
1890,  page  135)  has  described  factitious  coffee-beans  sold  under 
the  name  of  "  Kunst  Kaffee."  The  following  were  the  compositions 
of  the  samples  referred  to  above  : — 


Piyrthle. 

Konig. 

Fricke. 

Moisture,    . 

Proteids,      . 

Fat, 

Starch,  sugar,  gum,  &c.,    . 
Cellulose,     .... 
Caffeine,      . 
Ash,     .'      . 

1-46  per 

13-93        , 

3-86 
64-01        , 
15-83 

0-07        , 

2-53 

cent. 

5-14  per  cent. 

10-75        „ 

2-19 
76-76        „ 

3-96        „ 

1-20     *'„ 

(Analysed  after  dry- 
ing.) 

17-90  per  cent. 
2-03 

10-83  "*„ 
0-94        „ 
2-27        „ 

101-63  per  cent. 

100  00  per  cent. 

100-00  per  cent. 

Matter  soluble  in  water,    . 

21-53  per  cent. 

29-28  per  cent. 

24-85  per  cent. 

R.  W  0 1  f  f  e  n  s  t  e  i  n  (Zeitsch.  angew.  Chemie,  1890,  No.  3)  has 
described  two  varieties  of  factitious  coffee,  respectively  known  in 


IMITATION    COFFEE.  537 

OermaDy  as  Domkaffee  and  Allerweltkaffee.  Both  preparations 
were  entirely  destitute  of  caffeine.  One  consisted  practically  of 
chicory,  while  the  other  contained  large  quantities  of  lupines. 
From  the  latter  specimen  Wolffenstein  isolated  a  brown  colouring 
matter  having  the  spectroscopic  and  chemical  characters  of 
Cassella-hrown.  It  was  soluble  in  alkalies  and  in  water,  but  was 
completely  precipitated  from  its  solutions  by  hydrochloric  acid. 
Fourteen  grammes  of  the  sample  extracted  with  water  and  pre- 
cipitated with  acid  yielded  1*67  gramme  of  the  colouring  matter  (!). 

Factitious  coffee-beans  are,  with  very  rare  exceptions,  heavier 
than  water,  while  genuine  roasted  beans  are  invariably  lighter, 
unless  much  over-roasted.  In  taking  the  specific  gravity,  twenty 
beans  should  be  immersed  in  brine,  which  is  then  diluted  with 
water  till  ten  of  the  beans  float  and  the  remainder  sink.  The 
result  shows  the  average  density  ;  but  individual  factitious  beans 
often  vary  considerably  from  the  mean. 

In  genuine  coffee-beans  a  portion  of  the  fine  membrane  or 
"  parchment "  with  which  the  berries  were  invested  will  almost 
always  be  found  adhering  in  the  cleft.  The  microscopic  structure 
of  the  bean,  as  seen  in  a  thin  section,  or  of  the  powder  affords 
a  certain  means  of  recognising  its  nature.  Most  factitious  beans 
contain  starch,  which  is  entirely  absent  from  genuine  coffee. 
Ohicory  and  other  roots  are  readily  recognisable  by  the  microscope. 
The  methods  used  for  the  examination  of  ground  coffee  may  also 
be  applied. 

Dangway  beans,  the  seeds  of  Cassia  tora  or  C.  occidentalism 
abundant  in  British  Burmah,  have  been  prepared  and  patented  as 
a  substitute  for  coffee  {Eng.  Pat.,  15,564,  1888).  In  Germany,  the 
ground  and  roasted  seeds  have  been  sold  under  the  name  of 
"Mogdad  coffee,"  and  it  is  said  that  a  smaller  proportion  than 
20  per  cent,  in  coffee  cannot  be  detected  either  by  the  taste  or  the 
appearance  of  the  sample.  Dangway  beans  leave  about  10  per 
cent,  of  ash  on  ignition,  and  have  a  characteristic  microscopic 
appearance  which  has  been  described  and  illustrated  by  A. 
Wynter  Blyth  {Food  ;  Composition  and  Analysis).  They  sink 
very  rapidly  in  water  and  colour  brine  more  intensely  than  do  coffee 
beans.  Dangway  beans  contain  a  tannin  distinct  from  caffetannic 
acid.  They  are  destitute  of  caffeine,  but  0.  H  e  h  n  e  r  has  de- 
tected a  minute  quantity  of  some  other  alkaloid. 

The  use  of  Mussaenda  Borhonica  seeds,  to  be  mixed  and  roasted 
with  coffee-beans  or  entirely  substituted  for  them,  hai?  also  been 
patented  {Eng.  Pat,  14,945,  1888).^ 

^  Investigations  at  Kew  Gardens  show  the  supposed  Musscenda  seeds  to  be 
•really  those  of  Gcertnera  vaginata.     They  contain  no  caffeine. 


538  COMMERCIAL   CHICORY. 

The  beans  of  a  species  of  Phaseolus  are  reported  by  E.  F  r  i  c  k  e 
to  be  roasted,  ground,  and  sold  as  "  Congo  coffee."  The  berries 
are  very  large — 214  filling  a  100  c.c.  measure — and  of  shining 
black  colour.  The  infusion  is  very  astringent  and  contains  no 
caffeine  or  other  crystallisable  alkaloid. 

To  distinguish  lupine-seeds  from  coffee-beans,  Hager  treats 
3  grammes  of  the  powdered  sample  with  20  c.c.  of  water  and 
filters  after  half  an  hour.  The  filtrate  from  genuine  coffee  will 
be  feebly  yellow  and  not  taste  in  the  least  degree  bitter,  while 
in  the  presence  of  lupine-seeds  a  marked  bitter  taste  will  be 
observed. 

Ground  Coffee.  Besides  the  foregoing  sophistications  and 
substitutions  of  the  coffee-bean,  ground  coffee  is  liable  to  various 
adulterations.^  Some  of  these  can  be  tolerated  when  practised  in 
moderation,  provided  that  the  fact  and  proportion  of  admixture 
are  duly  acknowledged ;  but  it  must  be  remembered  that  all  these 
additions,  including  chicory,  the  least  objectionable  and  by  far 
the  most  widely  used,^  are  destitute  of  the  volatile  oil  and 
peculiar  alkaloid  which  give  to  coffee  its  most  valued  pro- 
perties. The  diminished  consumption  of  coffee  in  England  is 
doubtless  largely  due  to  the  frequency  and  extent  of  its 
sophistications. 

^  The  late  Dr  Wm.  Wallace,  writing  in  1884  {Analyst,  ix.  42),  names  the 
following  articles  as  used  for  adulterating  coffee  : — Chicory,  caramel,  dried  and 
roasted  figs,  dried  dates,  date-stones,  decayed  ship  biscuits,  beans,  peas, 
acorns,  malt,  dandelion  root,  turnips,  carrots,  parsnips,  and  niangold-wurzel. 
Damaged  raisins  are  stated  by  Albert  Smith  to  be  used  together  with  chicory 
for  making  French  coffee. 

2  CoMMEKCiAL  Chicory  is  prepared  from  the  root  of  Cichorium  iritybits, 
which  is  cut  into  slices,  kiln-dried,  and  then  roasted  in  the  same  manner  as 
coffee,  usually  with  the  addition  of  a  small  proportion  of  fat  of  some  kind. 
The  preparation  and  use  of  roasted  chicory  appears  to  have  originated  in 
Holland  about  1750.  A.  Mayer  {Bied.  OerUral.,  1885,  page  828)  gives  the 
following  as  the  composition  of  three  samples  of  Dutch  chicory  root : — Water, 
72 '00  to  77*3  per  cent.;  albuminoids,  1*1  ;  fat,  0*2;  inulin  and  other  non- 
nitrogenous  matters  insoluble  in  alcohol,  12-00  to  17 '3  ;  crude  fibre,  1'40  to 
1-8  ;  sugar,  &c.,  5*60  to  6*0  ;  bitter  extract,  0*05  to  0*15  ;  and  ash,  1*40  to 
1  '9  per  cent.  Mayer  found  the  bitter  substances  extracted  by  chloroform  to 
be  soluble  in  water  and  alcohol,  insoluble  in  ether,  and  absorbed  by  bone- 
charcoal.  They  were  decomposed  by  boiling  with  dilute  sulphuric  acid,  but 
did  not  by  such  treatment  yield  any  substance  capable  of  reducing  Fehling'a 
solution. 

A.  Petermann  {Bied.  Central. ,  1883,  page  843)  gives  the  following  results 
of  analyses  of  two  samples  of  roasted  chicory,  one  of  which  was  coarsely  and 
the  other  finely  ground.  The  ash  was  somewhat  higher  than  usual,  but 
was  perfectly  white.     The  fat  shown  was  probably  not  all  natural  to   the 


CARAMEL  IN   COFFEE. 


5m 


The  chief  adulterations  likely  to  be  met  with  in  ground  coffee 
are: — (1)  Mineral  matters;  (2)  roots,  such  as  chicory,  dandelion^ 
turnip ;  (3)  seeds  and  seed-products,  such  as  beans,  acorns,  and 
cereals ;  and  (4)  saccharine  matters,  such  as  caramel  and  roasted 
dates  and  figs. 

In  Bulletin  No.  29  of  the  Laboratory  of  the  Inland  Eevenue 
Department,  Canada,  the  chief  analyst,  T.  Macfarlane,  states  that : — 
"There  are,  moreover,  large  quantities  of  a  substance  imported 
under  the  name  of  essence  of  coffee,  for  adulterating  pur- 
poses, which  is  a  species  of  burnt  sugar,  and,  from  its  containing 
dextrin,  is  probably  made  from  some  of  the  bye-products  of  the 
glucose  factories.  It  costs  in  New  York  and  Philadelphia  from  3  to 
5  cents  per  lb.  As  it  possesses  no  organic  structure  it  is  apt  to  be 
overlooked  in  the  microscopical  examination.  It  contains  about 
75  per  cent,  of  matter  soluble  in  water,  which  has  great  colouring 
power,  and  a  little  of  it  is  capable  of  imparting  a  strong  brown 
coffee  colour  to  water." 

Caramel,  when  added  as  such,  may  often  be  distinguished  under 
a  low  microscopic  power  by  the  jet-black  colour  of  the  particles. 
These  dissolve  easily  in  water  with  intense  brown  colour,  and  the 
solution  has  a  bitter  taste. 

A  factitious  caramel  is  now  manufactured  by  adding  to 
glucose  about  one-eighth  of  its  weight  of  a  brown  coal-tar  dye, 
naphthol-hrown. 

A  useful  preliminary  test  for  ground  coffee  consists  in  gently 
strewing  some  of  the  powder  on  the  surface  of  cold  water.  The 
oil  contained  in  coffee  prevents  the  particles  from  being  readily 
wetted  by  the  water,  thus  causing  them  to  float.     Chicory  and  the 

chicory,  as  the  proportion  recorded  is  largely  in  excess  of  that  found  by  other 
observers.  The  water  also  is  much  above  the  usual  proportion  in  recently 
roasted  chicory  (5  to  7  per  cent.),  and  the  albumenoids  below  the  usual  rang& 
(8-75  to  11-50.— 0.  Hehner). 


Coarse  Grains. 

Fine  Powder. 

Water  (lost  at  lOO'-lOS"  C), 

Glucose,      ... 

Dextrin ;  inulin,                 .                       .       . 

Albuminoids, 

Colouring  matter  and  bitter  extractive, . 

Ash  in  soluble  portion, 

Ash  in  insoluble  portion, 

Albuminoids, 

Fat, 

Cellulose, 

16-28 

26-12 
9-63 
3-23 

16-40 

2-58 

4-58 

•15 

5-71 

12-32 

16 -96% 
23-76 1 

9.31?   Soluble  in 
>  hot  water 

17-591 
2-55/ 
b-S9\ 
2-98    Insoluble  in 

>-  hot  water 
3-92         =26-14. 

13-37^ 

540  DETECTION   OF   CHICORY. 

majority  of  coffee  adulterants  contain  no  oil,  and  their  caramel 
is  very  quickly  extracted  by  the  water,  with  production  of  a 
brown  colour,  while  the  particles  themselves  rapidly  sink  to 
the  bottom  of  the  water.^  On  stirring  the  liquid,  coffee 
becomes  tolerably  uniformly  diffused  without  sensibly  colouring 
the  water,  while  chicory  and  other  sweet  roots  quickly  give  a 
dark  brown,  turbid  infusion.  Eoasted  cereals  do  not  give  so 
distinct  a  colour. 

According  to  A.  Franz  (Arch.  Pharm.,  [5],  iv.  298),  if  2  c.c. 
of  a  10  per  cent,  infusion  of  coffee  in  boiling  water  be  treated  with 
0*3  c.c.  of  a  2J  per  cent,  solution  of  cupric  acetate,  and  the  liquid 
filtered,  a  greenish-yellow  filtrate  is  obtained.  If  chicory  be  simi- 
larly treated,  a  dark  red-brown  filtrate  results,  the  colour  of  which 
changes  on  standing.  Ten  per  cent,  of  the  adulterant  can  thus  be 
detected. 

The  colour  of  an  infusion  of  chicory  is  said  to  remain  unaltered 
on  addition  of  a  solution  of  ferric  chloride  or  sulphate,  while  the 
brown  colouring  matter  of  coffee  infusion  turns  green,  and  is  par- 
tially precipitated  as  bluish-green  flakes.  In  an  infusion  of  mixed 
chicory  and  coffee,  the  reagent  forms  a  precipitate,  and  leaves  the 
liquid  more  or  less  brownish-yellow.  The  deposition  of  the  pre- 
cipitate is  facilitated  by  rendering  the  liquid  slightly  alkaline  by 
ammonia  (Dingier^ s  poly t.  Jour.,  ccxi.  78). 

Albert  Smith  (Pharm.  Jour.,  [3],  xi.  568)  recommends,  for 
the  detection  of  chicory  in  coffee,  that  10  grammes  of  the  sample 
should  be  boiled  with  250  c.c.  of  water,  and  the  liquid  strained 
and  precipitated  with  a  slight  excess  of  basic  lead  acetate.  On 
allowing  the  precipitate  to  settle,  the  supernatant  liquid  will 
be  colourless  if  pure  coffee  has  been  under  treatment,  but  in 
presence  of  chicory  will  be  coloured  to  a  greater  or  less  degree 
according  to  the  proportion  present,  which  can  be  estimated  from 
the  depth  of  tint  by  a  process  similar  to  that  of  nesslerising 
water. 

The  three  foregoing  tests  are  occasionally  of  service  for  the 
examination  of  infusion  of  coffee  when  the  solid  article  is  not 
available,  but  they  cannot  be  regarded  as  so  satisfactory  as  the 
actual  recognition  of  the  adulterant  by  the  microscope. 

The  great  majority  of  seeds  likely  to  be  met  with  in  coffee 
contain  a  notable  quantity  of  starch.  This  is  true  of  beans,  peas, 
acorns,  and  all  cereals  and  products  therefrom.  Hence  if  starch  be 
absent,  the  freedom  of  the  coffee  from  all  this  class  of  adulterants 
is  certain.     If  present,  the  nature  of  the  admixture  can  usually 

^  If  a  funnel  be  used  for  the  above  test,  the  sunken  particles  may  be  readily 
let  out  and  examined  under  the  microscope. 


DETECTION  OF  STARCH  IN  COFFEE.         54] 

be  ascertained  by  a  microscopic  examination  of  the  prepared 
sample.^ 

For  the  detection  of  starch,  the  author  boils  the  coffee  for  a  few 
minutes  with  about  10  parts  of  water.  When  the  liquid  has 
become  perfectly  cold,  some  dilute  sulphuric  acid  is  added,  and 
then  a  strong  solution  of  permanganate  of  potassium  dropped  in 
cautiously,  with  agitation,  till  the  colouring  matter  is  nearly 
destroyed,  when  the  liquid  is  strained  or  decanted  from  the  dis- 
soluble matter.  On  now  adding  a  solution  of  iodine  to  the 
solution,  a  blue  coloration  will  be  produced  if  any  starch  be 
present.  As  little  as  1  per  cent,  can  be  readily  detected  in  this 
manner.^ 

Some  operators  employ  animal  charcoal  for  decolorising  the 
coffee  infusion  before  testing  for  starch.  The  addition  of  starch- 
holding  adulterants  to  coffee,  in  the  author's  experience,  is  rare, 
but  in  the  United  States  and  Canada  is  very  common,  the 
adulterants  there  found  including  wheat-flour  and  bran,  buck- 
wheat, barley,  maize,  peas,  pea-hulls,  &c.^ 

The  insoluble  matter  remaining  after  treating  the  coffee  with 
water  and  decolorising  with  permanganate  can  be  advantageously 
examined  under  the  microscope  for  chicory  and  other  non-starchy 
additions,  the  structure  of  which  is  more  readily  observed  after 
the  removal  of  the  colouring  matter. 

F.  M.  Rimmington  {Pharm.  Jour.^  [3],  xi.  529)  recom- 
mends, for  the  removal  of  colouring  matter,  that  the  sample  of 
coffee  should  be  boiled  for  a  short  time  with  water  containing  a 
little  carbonate  of  sodium.  After  subsidence,  the  liquid  is  poured 
off,  the  residue  washed  with  water,  and  then  treated  with  a  weak 
solution  of  bleaching  powder  until  decolorisation  is  effected,  which 
usually  occurs  in  two  or  three  hours.  The  real  coffee  will  then 
form  a  dark  stratum  at  the  bottom  of  the  beaker,  and  the  chicory 
a  light  and  almost  white  stratum  floating  above  it,  and  showing  a 
clear  and  sharp  line  of  separation. 

^  For  this  purpose  the  coflfee  should  first  be  exhausted  with  ether  to  remove 
fat,  and  then  treated  with  methylated  spirit  to  dissolve  the  colouring  matter. 
In  the  residue,  the  starch  and  other  structures  will  be  readily  perceptible. 

^  A  certain  famous  sample  of  coffee  alleged  to  contain  acorns  gave  the  author 
no  reaction  by  the  above  test,  but  after  the  addition  of  2  per  cent,  of  roasted 
acorns  the  test  showed  the  presence  of  starch  very  clearly. 

^  In  1875  a  large  seizure  was  made  in  the  east  of  London  of  a  mixture  of 
10  per  cent,  of  coffee  with  90  of  roasted  acorns.  Roasted  acorns  were  first 
placed  before  the  English  public  as  "  Pelotas  coffee,"  and  subsequently  as 
"  coffee  surrogate,"  but  the  manufacture  of  both  these  preparations  was  stopped 
by  the  excise. 


542 


DETERMINATION   OF  CHICOKY. 


Under  the  microscope,  chicory  is  readily  recognised  by  the 
peculiar  dotted  appearance  of  the  vessels,  often  occurring  in 
bundles,  and  by  the  characteristic  appearance  of  the  large  cells. 
Dandelion,  turnips,  and  other  sweet  roots  present  a  close  similarity 
to  chicory,  and  can  only  be  safely  distinguished  therefrom  by 
careful  microscopic  comparison  of  the  sample  with  the  actual  roots 
in  question. 

The  microscopic  appearance  affords  the  only  certain  means  of 
identifying  chicory  and  other  roots  in  coffee,  and  the  same  state- 
ment applies  to  saccharine  fruits,  such  as  roasted  figs,  dates, 
raisins,  &c.^ 

The  nature  of  an  adulterant  of  coffee  having  been  ascertained 
by  the  aid  of  the  microscope  or  other  means,  an  attempt  may  be 
made  to  deduce  the  proportion  present  from  the  chemical  composi- 
tion of  the  sample.  When  only  one  adulterant  is  present,  this  may 
sometimes  be  effected  with  a  fair  approximation  to  accuracy ;  but 
even  in  the  case  of  chicory  it  is  not  always  possible  to  ascertain 
the  proportion  within  a  somewhat  wide  limit.^ 

For  ascertaining  the  proportions  of  adulterants  in  coffee,  the 
only  chemical  distinctions  of  any  practical  value  are: — Certain 
constituents  of  the  ash;  the  proportion  of  fat  as  extracted  by 
ether  or  petroleum  spirit;  the  proportion  of  aqueous  extract, 


^  Printed  descriptions  of  microscopic  characters  are  of  little  value,  and 
drawings  are  often  misleading.  The  adulterants  of  coffee  are  best  examined 
as  transparent  objects  under  a  moderate  power,  and,  except  where  starch  is  to 
be  identified,  by  unpolarised  light. 

2  What  can  be  done  in  this  manner,  and  the  errors  liable  to  occur  in  practice 
with  deficient  methods  or  imperfect  manipulation,  is  apparent  from  the  following 
figures  obtained  in  1882  by  various  analysts  to  whom  exactly  similar  samples 
of  mixed  coffee  and  chicory  of  known  composition  were  submitted  {Analyst, 
vii.  76):— 


Actual    percentage    of  \ 
Chicory  in  sample,  .  f 

Percentage   of  Chicory 
reported. 

Somerset    House'* 

(Referees),       ^ 

A,    . 


10  per  cent. 

Not  more  than  2J 
per  cent. 

7  per  cent. 

7        „ 

5  to  10  per  cent. 

16  per  cent. 

Genuine. 

! /Upwards  of  10 
;  \     per  cent. 


per  cent. 


Not  less  than  35 
per  cent. 

31  per  cent. 

32  „ 
25  „ 
35  „ 
31 


Upwards  of 
cent. 


per 


37i  per  cent. 


Not  less  than  48 
per  cent. 

38  per  cent. 
34        „ 
50        „ 

47        „ 

50        „ 

Upwards  of  40  per 
cent. 


ADULTERANTS   OF   COFFEE. 


543 


as  deduced  from  its  weight  or  the  specific  gravity  of  the  solution ; 
the  colour  of  the  infusion;  and  the  proportion  of  c  a  f  f  e  i  n  e  in  the 
sample.  In  all  cases  of  importance  two  or  more  of  these  methods 
should  be  employed. 

A.  Smetham  {Analyst,  vii.  73)  obtained  the  following  range 
of  figures  by  the  analysis  of  seven  samples  of  roasted  coffee,  repre- 
senting typical  commercial  qualities  : — 


Moisture  (lost  at  100°  C), 
Oil  (ether  extract), 
Crude  fibre,  ^    . 

,,         ,,     in  sample  dried  at  100° 
Cellulose, 
Nitrogen, 

Total  ash,        .  .  , 

Soluble  ash,     . 
Ratio  of  total  ash  to  soluble,  . 


1*59  to  3*89  per  cent. 

10-13  ,,  12-13       „ 

70-84  „  74-60       „ 

73-71  „  75-70       „ 

26-34  ,,  34-40        „ 

2-14  „  2-38       „ 

4-08  „  4-63        , 

3-14  ,,  3-60       „ 

100  :72  „  100:82  „ 


The  following  analyses  by  C.  Krauth  {Ber.,  xi.  277;  Jour. 
Chem.  Soc,  xxxiv.  449)  give  some  comparative  figures  for  coffee 
and  its  more  probable  adulterants.  Except  in  the  case  of  the  last 
column,  the  results  apply  to  the  substances  previously  dried  at 
100°  :— 


Ash. 

Fat. 

Sugar. 

Insol. 

in 
Water. 

Moisture 

in 

IJndried 

Substance. 

Pre- 

existent 

After  1      in 
Boiling   Water, 
with    1 
Acid,  i 

Coflfee,     roasted,  five  1 
samples,    .        .       / 

4-19 
to  6-38 

11-76 
to  15-6 

}-0-2 

„,.„q/    22-47 
2*2^1  to  25-21 

74-79 
to  77-63 

1-47 
to  4-37 

Chicory,  roasted,   . 

10-83 

1-15 

23-40 

22-14        65-42 

34-58 

4-30 

Chicory,  unroasted, 
Rye,  roasted, 

5-35 
2-43 

43 

1-68 

23-84 

Not  de-      78-71 
termined. 
75-37        31-92 

21-28 
68-07 

6-89 
0-28 

Wheat,  roasted, 

1-80 

2-75 

... 

52-65 

47-35 

... 

Coffee,     with   10   per\ 
cent,  rye,   .       .       / 

4-31 

14-16 

•19 

29-65        25-98 

74-46 

2-15 

Coffee,    with    10    per\ 
cent,  wheat,      .       / 

5-10 

12-55 

2-30 

23-15        30-63 

1 

69-36 

2-30 

1  The  "crude  fibre"  was  determined  by  boiling  2  grammes  of  the  sampk 
with  three  successive  quantities  of  water,  and  washing  the  residue  on  a 
counterpoised  filter  till  the  washings  were  colourless,  when  it  was  dried  at  100° 
C.  and  weighed. 


644 


ADULTERANTS   OF   COFFEE. 


The   following  analyses   by   Konig  show  the  composition  of 
C(Ttain  adulterants  of  coffee  : — 


Chicory. 

Figs. 

Acorns. 

Rye. 

Water, 

1216 

18-98 

12-85 

15-22 

Nitrogenous  matters,    .      .      .      . 

6-09 

4-25 

6-13 

11-84 

Fat, 

2-05 

2-83 

4-61 

3-46 

Sugar 

15-87 

34-19 

8-05 

3-92 

Other  non-nitrogenous  matters, 

46-71 

29-15 

6-2-0 

55-37 

Cellulose, 

11-00 

7-16 

4-98 

5-35 

Ash 

6-12 

3-44 

2-12 

4-81 

Matters  soluble  in  water,    . 

63-05 

73-81 

... 

45-11  (?) 

The  following  table  shows  the  published  results  of  analyses  of 
coffee  substitutes  said  to  be  manufactured  respectively  from  acorns, 
rye,  and  barley  :^ — 


- — 

" Acorn  1 
Coffee." 

"  Rye  Coffee 
Substitute." 

"Barley 
Coffee." 

"  Barley 
Coffee." 

Water, 

12-85 

2-22 

3-45 

6-41 

Nitrogenous  matters,    .      .      .      . 

6-13 

11-87 

9-38 

10-56 

Fat. 

4-01 

3-91 

3-25 

1-04 

Sugar, 

8-01 

... 

> 

Starch,        

Dextrin,      .      • 

V    62-00 

8-34 
49-51 

-    70-13 

68-38 

Other  non-nitrogenous  matters, 

i 

9-83 

J 

Cellulose, 

4-98 

9-78 

4-25 

10-56 

Ash,     .      .      

2-02 

4-54 

3-36 

3-04 

Matters  soluble  in  water,    . 

... 

61-33 

31-20 

34-37 

Glucose    formed    by   boiling    with 
dilute  sulphuric  acid. 

}    - 

... 

69-28 

67-19 

Moscheles  and  S  t e  1  z  e  r  have  recently  published  complete 
analyses  of  several  coffee  substitutes  (Ohem.  Zeit.,  1892,  xvi.  281; 
Analyst,  xvii.  154).  One  of  these  contained  lupines  (which  they 
consider  a  very  reprehensible  addition),  and  another  was  destitute 

^  The  '  *  acorn  coffee  "  was  analysed  by  Konig,  who  found  from  20  to  30  per 
cent,  of  starch,  and  6  to  8  per  cent,  of  a  variety  of  tannic  acid.  The  "  rye 
coffee  substitute"  was  prepared  by  Behr  Bros.  The  analyses  of  "barley 
coffee  "  are  by  C.  K  o  r  n  a  u  t  h. 


ASH  OF  COFFEE. 


545 


of  coffee,  but  contained  0*31  per  cent,  of  caffeine,  due  to  the 
presence  of  powdered  kola-nut. 

The  ash  of  pure  coffee  is  generally  between  3  J  and  4  J  per  cent., 
rarely,  if  ever,  exceeding  5  per  cent.,  and  even  when  a  considerable 
proportion  of  chicory  is  present  it  seldom  rises  beyond  6  per  cent. 
Any  notably  higher  proportion  will  indicate  the  presence  of  a 
mineral  adulterant.  The  ash  should  be  white,  or  nearly  so,  any 
marked  red  tint  indicating  an  added  compound  of  iron. 

The  composition  of  the  ash  of  coffee  presents  some  marked 
differences  from  that  of  chicory,  as  is  apparent  from  the  following 
results  of  analyses  by  H.  Ludwig  {Arch.  Fharm.,  [3],  i.  482) 
and  James  Bell  (Foods,  ii.  46,  57). 


Coffee-beans. 
H.  Ludwig. 

Coffee-beans, 

Eight 

Samples. 

J.  Bell. 

Chicory  Root, 
Eight  Samples.    J.  Bell. 

Gneiss 
Soil. 

Limestone 
Sou. 

Deducting 
Si02  and  Sand. 

Including 
Si02  and  Sand. 

K20      ... 

14-13 

44-03 

53-20  to  55-80 

27-85  to  46-27 

24-88  to  33-88 

NaaO 

5-84 

5-85 

Not  detected 

3-17  „  16-90 

2-04  „  15-10 

CaO 

8-64 

4-89 

4-10  to    6-16 

7-65  „  10-81 

5-00  „     9-60 

M9O 

814 

8-01 

8-20  „    8-87 

5-33  „     8-08 

3-42  „     7-22 

FeaOs 

16-54 

1-96 

0-44  „    0-98 

3-50  „    8-29 

3-13  „     5-32 

P2O6 

18-65 

10-54 

10-15  „  11-60 

9-59  „  12-61 

6-65  „  11-27 

SO3   . 

15-28 

1-64 

3-09,,    5-26 

8-38  „  11-78 

5-38  „  10-53 

CI      . 

Trace 

0-98 

0-26  „     1-11 

5-03  „     6-08 

3-23  „    4-93 

CO2   . 

8-34 

21-24 

14-92  „  18-13 

2-04  „    4-60 

1-78  „    3-19 

SiOa 

1-65 

0-37 

0-00  „     0-45 

2-61  „  12-75 

Sand 

None 

None 

None 

... 

8-08  „  23-10 

T  ..  J • 

_    J?. 

3 

•__     1- 

i.--L1-      

i.    _r    ^_ 

J_ 14. 

Ludwig  found  in  each  case  a  notable  amount  of  soda,  a  result 
which  disproves  Bell's  improbable  statement  that  this  base  is 
absent  from  coffee-ash.  Ludwig's  figures  also  show  an  enormous 
variation  in  the  proportions  of  KgO,  FcgOg,  SO3,  and  COg,  accord- 
ing to  the  nature  of  the  soil  on  which  the  coffee-plant  is  grown.^ 
If  the  NagO  in  chicory-ash  be  calculated  into  its  equivalent  of 
KgO,  and  the  figure  thus  found  added  to  the  actual  KgO,  the  per- 
centage is  not  greatly  different  from  the  proportion  of  potash  found 


1  The  sample  of  coffee  from  a  gneiss  soil  must  be  regarded  as  highly  abnormal. 
In  the  wide  experience  of  the  author  the  ash  from  genuine  coffee  has  never 
been  observed  to  have  a  red  colour,  as  would  be  the  case  with  the  ash  of  a. 
specimen  containing  a  considerable  proportion  of  iron. 

VOL.  III.  PART  II.  2  M 


546 


ASH    OF   COFFEE. 


by  Bell  in  coffee-ash.  The  proportion  of  oxide  of  iron  is  notably 
greater  in  chicory  than  in  coffee.  Hence  chicory-ash  always  has 
a  red  tinge  which  is  absent  from  the  ash  of  genuine  coffee.  A 
notable  difference  is  observable  in  the  proportions  of  COg  and  CI, 
and  a  very  wide  distinction  in  the  figures  for  sand  and  silica.  In 
only  one  of  the  eight  samples  of  coffee  did  the  silica  even  approach 
0*5  per  cent.,  and  in  another  portion  of  the  same  coffee,  which  was 
properly  screened  before  roasting,  the  silica  of  the  ash  fell 
to  nil. 

In  consequence  of  the  large  proportion  of  potassium  carbonate 
in  coffee-ash,  the  percentage  of  the  total  ash  soluble  in  water  is 
much  greater  than  in  the  case  of  chicory-ash,  and  attempts  have 
been  made  to  utilise  this  fact  for  ascertaining  the  proportion  of 
chicory  present  in  mixtures  of  the  two.  Thus  the  author  found 
from  60  to  85  per  cent,  of  the  total  ash  of  coffee  to  be  soluble  in 
water,  whereas  on  an  average  only  34  per  cent,  of  the  total  ash 
of  chicory  was  soluble  in  water.  But  this  proportion  is  gravely 
affected  by  the  proportion  of  actual  sand  which  may  be  present. 
This  varies  in  commercial  chicory  from  a  trace  up  to  4*5  per  cent., 
which  difference  is  quite  sufficient  to  invalidate  deductions  based 
on  the  ratio  of  the  total  to  the  soluble  ash.  By  comparing  the 
soluble  ash  with  the  total  ash  minus  sand  and  silica,  somewhat 
more  reliable  results  are  obtained,  but  at  best  the  method  is  only 
"Capable  of  affording  a  rough  indication  of  the  proportion  of  chicory 
present.  It  may,  however,  serve  to  point  to  the  presence  of  a 
foreign  ingredient,  which  can  then  be  identified  and  determined  by 
other  means.  The  following  ash-analyses,  by  J  a  m  e  s  B  e  1 1,  are 
interesting  in  this  connection  : — 


Lupins. 

Acorns. 

Maize. 

Parsnips. 

Dandelion  Root. 

K20  .     .     . 

33-54 

54-93 

30-74 

56-54 

17-95 

NagO          .        . 

17-75 

0-63 

Not  found 

Not  found 

30-95 

CaO    . 

7-75 

6-01 

3-06 

6-85 

11-43 

MgO    . 

6-18 

4-32 

14-72 

6-49 

1-31 

FeaOs         .        . 

0-54 

0-84 

0-53 

1-27 

P2O6   .        .        . 

25-53 

11-15 

44-50 

13-84 

n-21 

SO3     .        .        . 

6-80 

4-79 

4-13 

4-07 

2-37 

ca     .     .      . 

211 

2-51 

0-50 

2-09 

3-84 

CO2   .     .     . 

0-56 

13-69 

... 

11-44 

6-21 

SiOa,  &c.    . 

0-87 

1-01 

1-78 

0-57 

11-26 

101-09 

99-58 

100-27 

102-42 

97-80 

The    following    centesimal    figures 
refer  to  the  ash  of  other  roots  :— 


by    Way    and     Ogston 


DENSITY   OF   COFFEE   INFUSION. 


647 


Turnip. 

Beet. 

Carrot. 

FeaOa    .       .       . 
CI          ... 
CO2       .       . 

0-14  to  0-66 

3  „  5 
9-5  „  15 

0-52  to  3-74 
85  „  30 
15  „  21-6 

0-59  to  1-66 
3  „  4-6 
15  „  19 

The  fat  of  co£fee  is  tolerably  constant  in  amount,  and  hence  the 
proportion  serves  as  a  useful  indication  of  the  amount  of  certain 
admixtures.  Thomas  Macfarlane,  Head  Chemist  of  the 
Inland  Revenue  Department,  Ottawa,  informs  the  author  that  the 
petroleum-ether  extract  from  previously  dried  coffee  ranges  from 
10  to  12  per  cent.  Only  one  sample  out  of  nearly  fifty  examined 
showed  less  than  10,  and  no  sample  gave  as  much  as  13  per  cent., 
although  12J  per  cent,  was  reached  in  a  few  instances.  Chicory 
yields  about  1  per  cent,  when  similarly  treated,  and  three  samples 
of  roasted  barley  gave  from  1*31  to  1'54  per  cent. 

The  aqueous  extract  of  coffee  is  remarkably  constant  in  amount, 
and  is  very  little  affected  by  variations  in  the  roasting.  Instead 
of  weighing  the  actual  extract,  Graham,  Stenhouse  and 
Campbell  {Jour.  Chem.  Soc.,ix.  38)  determined  the  specific 
gravity  of  the  aqueous  infusions  of  coffee  and  various  roasted 
vegetable  matters.  Their  method  was  to  treat  the  roasted  sub- 
stance with  ten  times  its  weight  of  cold  water,  raise  the  liquid  to 
the  boiling-point,  and  observe  the  density  of  the  filtered  liquid 
after  cooling  to  60°  F.  (  =  15-5°  C).  The  foUowing  is  a  classified 
arrangement  of  their  results  : — 


Specific  Gravity 

Specific  Gravity 

Substance. 

of  10  per  cent. 

Substance. 

of  10  per  cent. 

Infusion. 

Infusion. 

COFFBE :— 

Roots  :— 

Mocha, 

1008-0 

Chicory.Yorkshire, 

1019-1 

Neilgherry, 

1008-4 

„        English,  . 

1021-7 

Plantation  Ceylon, 

1008-7 

„        Foreign, . 

1022-6 

Java,     . 

1008-7 

„        Guernsey, 

1023-3 

Jamaica, 

1008-8 

Average, 

1021-05 

Native  Ceylon,     . 

1009-0 

Parsnips, 

1014-3 

Costa  Rica,  . 

1009-0 

Carrots, 

1017-1 

Costa  Rica,  . 

1009-05 

Turnips, 

1021-4 

Average,    . 

1008-7 

Dandelion,    . 

1021-9 

Red  beet,      . 

1022-1 

Leguminous  Seeds:— 

Mangold  wurzel,  . 

1023-5 

Lupins, 

1005-7 

Peas,     . 

1007-3 

Cereal  Products  :— 

Beans,  . 

1008-4 

Brown  malt, 

1010-9 

Black  malt,  . 

1021-2 

Miscellaneous  :— 

Rye  meal,     . 

1021-6 

Spent  tan,     . 

1002-1 

Maize,  . 

1025-3 

Acorns, 

1007-3 

Bread  raspings,    . 

1026-3 

548  DENSITY  OF   COFFEE   INFUSION. 

These  results  show  a  marked  distinction  between  cofifee,  legu- 
minous seeds,  and  acorns  on  the  one  hand,  and  cereal  products  and 
chicory  and  other  roots  on  the  other.  Unfortunately,  with  the  ex- 
ception of  chicory  and  coffee,  they  apply  merely  to  single  speci- 
mens of  each  kind  of  substance. 

Experiments  made  in  the  author's  laboratory  gave  a  mean 
density  for  coffee-infusions  precisely  identical  with  that  obtained 
by  Graham,  Stenhouse  and  Campbell  (1008"7).  Operating  as  they 
prescribe,  however,  there  is  always  a  suspicion  that  the  exhaustion 
is  incomplete,  especially  in  the  case  of  genuine  coffee  which  has 
not  been  very  finely  ground.  Hence  in  a  series  of  experiments 
made  in  the  author's  laboratory,  the  sample  of  coffee  was  well 
boiled  with  10  parts  of  water,  the  solution  filtered,  and  the  residue 
washed  with  hot  water  till  the  filtrate  measured  10  c.c.  for  every 
1  gramme  of  the  substance  employed.  Operating  in  this  manner, 
the  infusions  from  fourteen  specimens  of  ordinary  commercial  roasted 
coffee  (ground  in  the  laboratory)  were  found  to  have  a  specific 
gravity  ranging  from  1006*8  to  1008*5,  with  an  average  of 
1007-9  1  (Analyst,  v.  1). 

J.  Skalweit  has  shown  that  the  specific  gravity  of  the 
aqueous  infusion  is  not  sensibly  affected  by  the  extent  to  which 
the  coffee  has  been  roasted. 

By  the  exhaustion-process,  the  author  obtained  the  following 
results  from  samples  of  commercial  chicory  (undried) : — 

Specific  Gravity 
of] 


Yorkshire  Chicory,  under-roasted, 

,,  ,,        (same  sample),  highly  roasted, 

Chicory  of  unknown  origin,  .... 


10  per  cent. 
Infusion. 

1025-9 

1019-0 

1021-1 

1020-0 

1023-4 


1021-9 

It  is  evident  that  the  density  of  chicory  infusions  varies  much 
more  than  that  of  coffee,  a  fact  which  prevents  the  method  from 
furnishing  more  than  an  approximate  determination  of  the  propor- 
tion of  coffee  and  chicory  in  a  mixture  of  the  two.  A  sharper 
result  may  be  obtained  by  previously  drying  the  sample  at  100°, 

^  This  figure  is  somewhat  lower  than  the  average  of  Graham,  Stenhouse,  and 
Campbell's  experiments,  which  tends  to  show  that  they  effected  practically 
perfect  exhaustion.  The  difference  is  not  improbably  due  to  a  slight  loss  by 
evaporation  when  the  infusion  is  made  by  raising  the  liquid  to  the  boihng- 
point,  instead  of  boiling  thoroughly  and  making  the  infusion  up  to  a  definite 
measure  after  cooling.  0.  H  e  h  n  e  r  has  met  with  a  genuine  coffee  giving  an 
infusion-density  of  1010-2. 


DETERMINATION  OF  CHICORY. 


649 


and  hence  eliminating  the  somewhat  serious  error  due  to  varying 
l)roportions  of  moisture.  Adopting  1024  as  the  normal  gravity 
of  the  infusion  of  dried  chicory  and  1009  as  that  of  dried  coffee, 
the  percentage  of  real  coffee  in  a  mixture  of  the  two  will  be  found 
by  the  following  equation,  where  d  is  the  specific  gravity  of  the 
10  per  cent,  infusion  and  C  the  percentage  of  coffee  in  the  sample: — 


C- 


(1024 -<^)  100 
15 


A.  M^Gill  {Trans.  Royal  Soc.  Canada,  1887)  finds  that  the 
density  of  the  infusions  of  coffee  and  chicory  is  materially  affected 
by  the  fineness  of  the  powder,  the  time  occupied  in  heating  the 
decoction  to  boiling,  and  the  time  during  which  the  boiling  with 
water  is  continued.  He  recommends  that  a  weight  corresponding 
to  10  grammes  of  the  moisture-free  sample  should  be  boiled  with 
100  c.c.  of  distilled  water  in  a  flask  fitted  with  a  reflux  condenser. 
The  heat  is  adjusted  so  that  ebullition  commences  in  ten  to  fifteen 
minutes,  and  the  boiling  is  continued  exactly  one  hour,  when  the 
flame  is  removed,  and  after  fifteen  minutes'  rest  the  liquid  is  passed 
through  a  dry  filter.  The  average  density  of  a  10  per  cent, 
decoction  of  pure  coffee  thus  prepared  was  found  to  be  1009*86 
at  62°,  the  mean  number  for  chicory  decoction  (three  samples) 
being  1028*21  at  the  same  temperature,  or  a  difference  of  18*35.^ 
From  these  results  the  following  formula  may  be  deduced : — 

(1028-21-(Zat62°F.)100 
18-35 

^  Thos.  Macfarlane,  Chief  Analyst  in  the  Inland  Revenue  Laboratory, 
Ottawa,  has  communicated  to  the  author  the  following  results,  obtained  by 
the  application  of  M^Gill's  method  for  ascertaining  the  infusion-density  and 
actual  determination  of  the  soluble  extract.  This  last  determination  was  made 
by  thoroughly  extracting  the  dried  sample  with  petroleum  ether,  and  then 
treating  the  redried  substance  with  boiling  water.  Instead  of  evaporating  the 
solution,  the  insoluble  matter  was  redried  and  weighed,  the  loss  showing  the 
**  water  extract " : — 


Sontas  Coffee, 

Mocha  Coffee, 

Java  Coffee 

,,  with  10  per  cent.  Chicory, 

,,    20 


Chicory, 


Water  Extract. 


22-44 
21-92 
26-42 
25-90 
30-75 
37-40 
43-36 
49-84 
53-82 
60-34 
65-93 
71-41 
77-73 


Infusion  Gravity 
»t  62°  F. 


1009-78 
1009-73 
1011-58 
1013-44 
1015-28 
1017-08 
1018-66 
1020-48 
1022-70 
1024-15 
1026-42 
1028-32 


550  DETERMINATION   OF   CHICORY. 

It  is  evident  that  the  specific  gravity  of  the  aqueous  infusion  is 

really  a  function  of  the  solid  matter  dissolved  by  the  water,  and  a 

close  approximation  to  the  percentage  of  the  latter  can  be  obtained 

by  dividing  the  difference  between  the  solution-density  and  1000 

by  the  number  0*375  or    multiplying  it    by  2-67.1      Thus  if  a 

coffee-infusion  have  a  density  of  1009*0,  the  proportion  of  matter 

soluble  in  water  will  be 

1009-0-1000-0    „,  ^  . 

0^376 24-0  per  cent. 

The  figures  for  soluble  extract  obtained  by  T.  Macfarlane 
(Ottawa)  by  the  analysis  of  54  samples  of  commercial  coffee  ranged 
from  21*5  to  26*5  per  cent.,  with  an  average  of  about  24  per  cent.^ 
The  samples  were  dried  at  100°,  deprived  of  fat  by  treatment  with 
petroleum  ether,  re-weighed,  and  then  exhausted  with  water. 
Instead  of  evaporating  the  infusion  and  weighing  the  soluble  extract, 
the  insoluble  residue  was  dried  and  weighed,  and  the  loss  gave  the 
soluble  extract.  A.  Smetham  has  also  proposed  to  wash,  dry, 
and  weigh  the  insoluble  matter  left  on  the  filter. 

Alfred  E.  Johnson  states  the  soluble  extract  from  previ- 
ously dried  (roasted)  coffee  to  be  very  constant  at  24  per  cent., 
and  the  extract  from  dried  chicory  to  average  70  per  cent.,^  and 
on  these  figures  bases  the  following  process  for  the  analysis  of 
coffee  mixtures. 

The  ground  coffee  is  dried  at  100°  C.  and  5  grammes  weight  of 
the  moisture-free  sample  boiled  for  fifteen  minutes  with  200  c.c. 
of  water.  After  settling  for  a  few  minutes,  the  liquid  is  poured  off 
through  copper  wire-gauze  or  coarse  muslin  into  a  250  c.c.  flask. 
The  grounds  are  boiled  with  50  c.c.  of  water  for  five  minutes  and  the 
liquid  strained  as  before.  The  contents  of  the  flask  are  cooled,  made 
up  to  250  c.c,  agitated,  and  poured  on  to  a  dry  filter.  Fifty  c.c. 
of  the  filtrate,  rejecting  the  first  portion  (equal  to  1  gramme  of  the 
dry  sample),  is  then  evaporated  in  a  flat  dish  over  boiling  water, 

^  This  factor  is   deduced  from  the  known  solution-densities  of  caramel 
and  the  carbohydrates.     J.  Skalweit  {Rep.  Anal.  Ghem.,  1882,  page  227), 
as  the  result  of  direct  experiment,  gives  the  following  data: — 
At  17 '5"  C,  I'OOl  sp.  gr.  of  20  %  infusion  represents  0'36  extract  per  100  c.c. 
1-115  ,,  „  „  27-24        „ 

1'235  „  „  „  48-25 

2  The  purity  of  some  of  these  samples  was  doubted,  and  Macfarlane 
considers  22*0  per  cent,  to  represent  more  accurately  the  usual  proportion 
of  extract  yielded  by  genuine  coffee. 

^  0.  Hehner  found  a  lightly-roasted  chicory  (dried)  to  give  Ql  '1  per  cent,  of 
soluble  matter,  and  an  infusion-density  of  1024*4,  while  a  highly-roasted  sample 
had  an  infusion-density  of  1019,  and  yielded  only  54*1  per  cent,  of  extract. 


COLOUR  OF  COFFEE  INFUSION.  551 

and  the  residue  (representing  the  extract  from  1  gramme)  dried  in 
the  water-oven  and  weighed.     Then : — 

100  (70 -per  cent,  of  extract  found)  .  „     „»     . 

^ .X ^  —  percentage  of  coffee  m  sample. 

The  results  thus  yielded  by  coffee  and  its  principal  adulterants 
are  given  on  pages  543,  544. 

The  tinctorial  poicer  of  the  infusion  was  suggested  by  Graham, 
Stenhouse  and  Campbell  {Jour.  Chem.  Soc,  ix.  36)  as 
a  means  of  determining  adulterants  in  coffee.  They  found  that 
the  depth  of  colour  of  the  liquid  obtained  by  infusing  coffee  and 
its  adulterants  in  2000  times  their  weight  of  boiling  water  varied 
remarkably,  caramel  giving  about  seven  times  and  chicory  about 
three  times  as  deep  a  colour  as  coffee.^  But  their  experiments 
showed  that  four  different  samples  of  pure  coffee  varied  in  tinctorial 
power  between  143  and  183,  as  compared  with  caramel  as  1000, 
and  no  doubt  samples  of  chicory  would  be  found  to  present  at  least 
as  great  difference  in  colouring  power,  according  as  they  happened 
to  be  lightly  or  strongly  roasted.  Nevertheless  the  author  found 
{Chem.  News,  xxix.  140)  that  the  tinctorial  power  of  an  infusion  of 
mixed  samples  of  chicory  was  almost  exactly  three  times  that  of  an 
infusion  of  average  or  mixed  coffee,  and  that  different  samples  of 
chicory  did  not  vary  more  than  from  2*8  to  3'2  in  colouring  power 
when  compared  with  the  same  sample  of  coffee.  In  order  to 
estimate  the  proportion  of  chicory  in  a  sample  of  coffee  mixture,  a 
standard  mixture  should  be  prepared  by  mixing  together  several 
representative  samples  of  genuine  ground  coffee  with  an  equal 
weight  of  mixed  chicory.^  One  gramme  of  this  standard  coffee 
mixture  (containing  50  per  cent,  of  coffee),  and  the  same  weight  of 
the  sample  to  be  tested,  are  boiled  for  a  few  minutes  with  20  c.c. 

^  The  following  are  the  relative  amounts  of  various  roasted  substances  found 
by  Graham,  Stenhouse,  and  Campbell  to  impart  an  equal  depth  of  colour  to 
the  infusion  : — 


Caramel, 

.      1-00 

Mangold  wurzel, 

.      1-66 

Black  malt, 

1-82 

White  tiirnjps,    . 

.      2-00 

Carrots, 

.      2-00 

Chicory  (darkest  Yorks),  2-22 


Coffee,  .  .  5-46  to  6-96 
White  lupin-seed,  .  lO'OO 
Beans  and  peas,  .  IS-SS 
Spent  tan,  .  ,  .  33-00 
Brown  malt,        .        .40-00 


Parsnips,   .  .      2-50 

Maize  and  rye,  .      2-86 

Dandelion  root,  3-33 

Red  beet,  .        .  .      3-33 

Bread  raspings,  .      3-64 

Acorns,      .  .5-00 

2  If  the  standard  coffee  mixture  be  kept,  it  undergoes  a  change  which  modi- 
fies, even  in  a  dry  state,  the  colour  of  the  infusion.  A  permanent  standard  of 
the  right  tint  can  be  made  by  mixing  solutions  of  ferric,  cobalt,  and  copper 
sulphates  in  proper  proportions.  The  yellowish-brown  glass  employed  in 
Lovibond's  tintometer  for  the  colorimetric  determination  of  carbon  in  steel  can 
also  be  employed  as  a  standard,  if  its  value  be  previously  ascertained.  The 
tints  are  best  observed  by  placing  a  piece  of  wet  filter-paper  behind  the  tubes 
while  they  are  held  up  to  the  light. 


552  CAFFEINE   IN   COFFEE. 

of  water.  The  liquids  are  cooled  and  passed  through  a  double 
filter,  the  insoluble  portions  being  repeatedly  boiled  with  fresh 
quantities  of  water  till  no  more  colour  is  extracted.  The  solution 
of  the  standard  mixture  is  then  made  up  with  water  to  200  c.c, 
and  the  solution  of  the  sample  to  100  c.c.  Ten  c.c.  of  this  latter 
liquid  is  poured  into  a  narrow  graduated  tube,  and  some  of  the 
standard  solution  into  another  tube  of  exactly  equal  bore.  If  the 
sample  consists  of  pure  coffee,  the  two  liquids  will  now  be  of 
exactly  similar  tint ;  but  if  chicory  be  present,  the  solution  of  the 
sample  will  be  the  darker,  in  which  case  water  is  gradually  added 
till  the  tints  are  precisely  equal.  When  this  point  is  attained,  the 
volume  of  the  sample  solution  is  observed.  Every  1  c.c.  of  water 
added  represents  5  per  cent,  of  chicory  in  the  sample.  Thus  if  the 
liquid  measure  17  c.c,  the  sample  contains  35  per  cent,  of  chicory. 

J.  R.  Leebody  {Chem.  News,  xxx.  243)  has  described  a 
similar  method,  but,  instead  of  observing  the  colour  of  the  solutions 
transversely,  he  dilutes  the  solution  from  1  gramme  of  the  coffee  to 
700  c.c.  and  observes  the  colour  from  above,  as  in  nesslerising  water. 

The  observation  of  the  infusion-colour  is  occasionally  very  useful 
as  an  indication  of  the  presence  of  caramel  added  as  such,  since  in 
that  case  the  colour  wiU  be  greatly  in  excess  of  the  proportion  of 
chicory  or  other  adulterant  as  deduced  by  other  methods. 

The  caffeine  of  coffee  is  tolerably  constant  in  amount,  and  hence 
its  determination  has  been  recommended  by  Paul  and  C  o  w  n  1  e  y 
(Pharm.  Jour.,  [3],  xvii.  565,  648,  821,  921)  as  means  of  estimat- 
ing the  proportion  of  real  coffee  in  a  mixture.  These  chemists 
have  shown  (page  492)  that  most  of  the  published  methods  for  the 
determination  of  caffeine  give  results  more  or  less  below  the  truth, 
but  that  when  the  process  recommended  by  them  is  adopted  the 
proportion  of  caffeine  isolated  varies  within  comparatively  narrow 
limits.  This  is  especially  the  case  if  the  roasted  berries  are  dried 
at  100°  before  grinding  them,  as  by  this  means  the  error  due  to 
variable  proportions  of  water  is  eliminated,  and  the  coffee  can  be 
obtained  in  a  finer  state  of  division,  and  hence  be  more  perfectly 
exhausted.  In  fourteen  commercial  samples  of  coffee-berries,  Paul 
and  Cownley  found  the  moisture  to  vary  from  6'2  to  lO'O  per  cent. 
After  drying  at  100°  C.  the  caffeine  ranged  from  1-20  (in  a  coffee 
from  Coorg)to  1*29  per  cent,  (found  in  coffee  from  several  sources), 
except  in  Liberian  coffee,  which  yielded  1-39  per  cent.  On  the 
basis  of  1-3  per  cent,  of  caffeine  in  genuine  coffee,  adopted  by  Paul 
and  Cownley,  the  proportion  of  real  coffee  in  a  mixture  will  be 
found  by  dividing  the  percentage  of  alkaloid  found  into  130.  It 
would  be  safer  to  adopt  the  number  120  instead  of  130,  and  in 
using  the  method  great  care  is  necessary  to  effect  the  isolation  of 


COFFEE   EXTRACT. 


553 


the  whole  of  the  caffeine.  To  ensure  this,  the  sample  must  be  in 
very  fine  powder,  the  exhaustion  by  alcohol  of  the  mixture  of 
coffee  with  lime  or  magnesia  must  be  proved  to  be  complete,  and 
the  agitation  of  the  aqueous  liquid  with  chloroform  must  be  repeated 
until  no  more  alkaloid  is  extracted. 

Although,  when  taken  alone,  any  one  of  the  foregoing  methods 
of  examining  coffee  is  liable  to  lead  to  determinations  of  the  pro- 
portion of  adulterants  somewhat  wide  of  the  truth,  by  the  combined 
use  of  several  a  fairly  accurate  deduction  can  be  made.  In  certain 
rare  cases,  additional  information  may  be  obtained  from  the  deter- 
mination of  the  fatty  matters,  the  alkalinity  of  the  soluble  ash, 
and  the  proportion  of  nitrogen. 

Coffee  Extracts  are  prepared  with  very  limited  success  by 
subjecting  roasted  coffee  to  treatment  with  boiling  water  or  steam, 
and  adding  the  volatile  products  to  the  aqueous  extract.  The 
product  is  deficient  in  caffeine,  and  does  not  contain  all  the 
extractive  matter  of  the  coffee ;  nor,  when  diluted  with  the  appro- 
priate amount  of  water,  is  the  colour  the  same  as  that  of  the 
freshly-prepared  liquid.  To  remedy  this  defect  caramel  is  added, 
together  with  strong  alcohol  as  a  preservative.  In  one  patent, 
addition  of  chicory  and  sugar  is  prescribed.  The  following  results 
were  obtained  by  A.  D  o  m  e  r  g  u  e  by  the  examination  of  six 
samples  of  coffee  extract : — 


Water. 

Extract  dried  at 
100°  C. 

Caflfeine. 

Ash. 

A,     .       .       . 

86-3 

13-7  per  cent. 

0-106  per  cent. 

0-61  per  cent. 

B,     .      .       . 

82-4 

17-6       ,, 

0-105        „ 

0-79        „ 

C,     .      .      . 

58-99 

41-01      „ 

0-060        „ 

4-30        „ 

D,     .      .       . 

72-8 

27-2        „ 

0-040       „ 

3-10        „ 

E,     .       .       . 

69-9 

30-1        „ 

0-050        „ 

1-40        „ 

F,     .       .       . 

80-74 

19-26      „ 

0-096        „ 

1-83        „ 

Samples  A  and  B  were  prepared  in  the  laboratory.  C,  D,  and 
E  were  coloured  with  caramel.  Domergue  regards  the  proportion 
of  caffeine  as  the  best  indication  of  the  value  of  a  coffee  extract. 

Of  three  samples  of  "  coffee  extract "  examined  by  G.  L. 
Spencer,  one  was  destitute  of  caffeine,  but  contained  cereals 
and  other  starchy  bodies;  a  second  contained  1*19  per  cent,  of 
caffeine,  or  about  as  much  as  ordinary  coffee ;  and  a  third  was  a 
mixture  of  coffee  extract  with  milk  and  sugar,  and  contained  0*72 
per  cent,  of  caffeine.  Very  notable  proportions  of  tin  and  copper 
were  detected  in  these  preparations. 


554  KOLA  NUTS. 

Kola -nuts. ^ 

The  Gourou  or  Kola-nut,  from  a  tree  belonging  to  the  family 
Sterculiaceoe,  is  chewed  and  used  for  preparing  a  beverage  in  Western 
Africa,  by  the  negro  inhabitants  of  the  West  Indies,  Brazil,  &c. 

From  the  nut  of  Sterculia  or  Cola  acuminata,  the  female  or  true 
Kola,  H  e  c  k  e  1  and  Schlagdenhauffen  {Pharm.  Jour.,  [3],, 
xiv.  584)  obtained  the  following  products : — 

Caffeine,      .  .  2 '3  48  per  cent, 

lilxtracted  by      J    Theobromine,  .  0'023 

Chloroform:— I    Fats,  .         .  .  0*585 

Tannin,        .  .  0027 

'  Tannin,  .  .     1-591 

Extracted  by     J    Kola  red,  .  .     1*291 

Alcohol: —        I    Glucose,  .  .2-875       „ 

Salts,  .  .     0-070 

(Starch,  .  .  33754 

Gum,  .  .     3040       „ 

Colouring  matters,     2*561       „ 

unaissoivea: — n    Proteids,  .  .     6-761        ,, 

J   CeUulose,  .  .  29830       „ 

I   Ash,  .  .     3-325       „ 

I   Water,  .  .   11919 

Accordmg  to  E.  Knebel  {Apoth.  Zeit.,  1892,  p.  112),  kolar 
nuts  contain  a  glucoside,  k  o  1  a  n  i  n,  which  on  boiling  with  water,. 
or  by  treatment  with  dilute  acids,  splits  up  into  caffeine, 
glucose,  and  k  o  1  a  -  r  e  d,  C-^fl^^{OH.)i:^.  This  last  product  is 
an  extremely  unstable  substance,  taking  up  oxygen  during  the 
drying  of  the  nuts,  with  separation  of  water  and  formation  of 
gallotannic  acid,  Ci^HjqOq.  It  is  stated  that  fresh  kola- 
nuts  have  a  greater  physiological  activity  than  when  dried,  as  in 
the  former  condition  the  kolanin  has  not  undergone  the  degenera- 
tion which  destroys  it  and  renders  the  caffeine  insoluble. 

M  0  n  a  r  0  n  and  P  e  r  r  o  n  e  state  that  powder  and  extract  of 
kola-nuts  have  a  far  greater  power  of  diminishing  the  elimination 
of  phosphates  and  nitrogen  than  caffeine  alone  has.     Kola-red  has 

^  Kola-nuts  are  oblong,  three  forming  a  ball  fully  2  inches  in  diameter, 
and  resembling  a  very  large  horse-chestnut.  The  individual  nuts  have  a 
rugged,  dark  brown  surface.  Inside  they  are  light  brown,  becoming  rusty  on 
exposure,  and  tough  as  wood.  When  fresh  the  taste  is  first  sweet,  then 
astringent,  and  finally  bitter.     After  drying  the  bitterness  diminishes. 

Various  other  African  plants  yield  seeds  closely  resembling  the  true  Kola, 
but  it  is  doubtful  whether  they  contain  caffeine. 


GUARANA.  555 

a  diminishing  influence,  but  both  it  and  caff'eine  act  better  in  their 
natural  combination  than  separately.  Caffeine  has  a  diuretic 
action,  whereas  kola  is  anuretic.  The  drug  prevents  waste  of 
brain  as  well  as  of  muscular  tissue. 

False  Kola,  Male  Kola,  or  Kola  Bitter,  is  the  seed  of  Garcinea 
kola,  a  plant  of  the  family  of  the  Cruttiferce  growing  in  Liberia 
and  Central  Africa.  On  extracting  the  seeds  with  chloroform, 
ether,  and  alcohol,  no  caff'eine  is  obtained,  but  only  resins.  One  of 
these  gives  a  violet  coloration  with  ferric  salts,  while  the  other  is 
dextro-rotatory  and  precipitated  by  tartar  emetic  and  basic  lead 
acetate.  The  physiological  action  of  the  extract  of  kola  bitter  is 
attributable  to  these  resins. 

Guarana.^ 

This  product  occurs  in  the  form  of  cylinders.  It  is  an  inde- 
finite mixture  of  various  materials,  of  which  the  seeds  of  PaulUnia 
sorhilis  appear  to  be  the  only  constant  and  characteristic  ingredient. 
It  is  prepared  by  the  Guaranis,  a  tribe  of  half -savage  Indians  on 
the  Upper  Amazon.  Its  only  interest  is  as  a  source  of  caffeine,  of 
which  it  contains  a  notable  proportion.  Sten house  obtained 
5-04,  and  F.  V.  Green  5*05  per  cent.  E.  R.  Squibb  found 
4 '8 3  per  cent.  {Ephemef-is,  ii.  615).  J.  H.  Feemster  (Pharm. 
Jour.,  [3],  xiii.  363)  obtained  from  3*9  to  5*0  per  cent,  of  caffeine 
from  five  samples  of  guarana.  The  alkaloid  is  readily  isolated  in  a 
state  of  purity  by  boiling  the  substance  with  water  and  litharge 
for  some  hours,  or  until  the  liquid  is  colourless  and  the  deposit 
settles  readily,  concentrating  the  filtered  liquid,  and  agitating  with 
chloroform. 

Cocoa  and  Chocolate. 

Cocoa  is  the  seed  of  the  tree  Theohroma  cacao  and  allied 
species  growing  wild  in  tropical  America.  It  is  cultivated  in 
Brazil,  Grenada,  Trinidad,  &c.,  and  has  been  introduced  into  the 
East  Indies  and  parts  of  Africa  and  Australia.  The  cocoa-seeds 
from  diff'erent  districts  vary  considerably  in  appearance  and  flavour, 
but  do  not  present  any  sharp  distinctions  in  chemical  composition. 

The  fruit  of  the  cocoa  contains  from  25  to  40  seeds  closely 
packed  in  the  pulp,  which  is  removed  by  subjecting  the  seeds  to  a 
process  of  fermentation  for  a  few  days.  The  pulp  is  then  separated 
by  hand,  and  the  seeds  placed  in  trays  and  dried  slowly  in  the  sun 
or  by  artificial  heat,  being  turned  over  at  intervals.     The  flavour 

1  Throughout  Brazil,  and  in  all  parts  of  South  America  where  the  prepara- 
tion is  used,  the  word  guaran&  is  universally  accented  on  the  last  syllable^ 
and  never  pronounced  guarana. 


556 


COMPOSITION   OF   RAW   COCOA. 


of  the  cocoa  is  greatly  dependent  on  the  care  and  skill  with  which 
the  operations  of  fermentation  and  drying  are  conducted.  The 
process  has  been  compared  to  the  malting  of  barley,  germination 
taking  place  and  being  subsequently  arrested.  It  is  alleged  that 
the  alkaloid  is  formed  during  the  process  of  fermentation,  but  the 
statement  requires  confirmation.-^ 

When  quite  dry,  the  cocoa-seeds  are  ready  for  exportation, 
but  before  being  used  they  are  subjected  to  a  gentle  roasting, 
whereby  the  bitter  taste  is  modified  and  the  kernels  are  more 
readily  separated  from  the  shells  or  husks,  which  constitute  from 
8  to  14  per  cent,  of  the  entire  seed.  When  separated  from  the 
husks  the  broken  kernels  are  known  as  cocoa-nibs. 

K  0  n  i  g  has  published  analyses  of  eight  samples  of  decorticated 
cocoa-beans  and  of  the  husks  from  the  same  specimens.  The 
following  figures  show  his  average  results  :  — 


Moisture. 

Nitrogenous 
Matters. 

1 
Fat.      Starch. 

Cellu- 
lose. 

Ash. 

Cocoa-beans  freed  from\ 
shell,   ..../" 

Cocoa-husks, 

3-25 
7-83 

14-76 
14-29 

49-00   \    13-31 
6-38 

3-68 
14-69 

3-65 
7-12 

The  following  analyses  of  raw  cocoa  are  byBoussingault 
{Ann.  Ghim.  Phys.,  [5],  xxviii.  433) : — 


Kernel. 


Kernel. 


Husk. 


Water,  .       ,       . 

Theobromine,     . 

Albuminoids, 

Asparagin,    . 

Fat,        .       .      . 

Soluble  cellulose, 

Starch  and  glucose, 

Gum, 

Tartaric  acid,*   . 

Tannin,  . 

Ash,       .      .      . 

Undetermined,  . 


7-6 

3-3 

10-9 

trace 

49-9 

10-6 

2-4 

2-4 

3-4 

0-2 

4-0 

5-3 


11-6 
2-4 
12-9 

53-0 

}  .1 
}  - 


12-18t 
14-26 
3*9 

12-12 
6-05 


*  The  presence  of  tartaric  acid  in  cocoa  has  been  confirmed  by  Weigmann,  who 
found  from  4*34  to  5-82  per  cent,  in  the  raw  whole  beans.  To  determine  it,  he  neutralised 
the  aqueous  extract  with  ammonia,  added  calciimi  chloride,  redissolved  the  precipitate 
in  hydrochloric  acid,  and  reprecipitated  with  soda. 

t  This  proportion  of  water  seems  improbably  high. 

^  The  author  mclines  to  the  opinion  that  the  alkaloid  of  tea  is  in  great 
measure  a  product  of  the  decomposition  of  some  more  complex  body,  as  has 
been  proved  to  be  the  case  with  the  caffeine  of  cola-nuts.  It  appears  not 
improbable  that  the  same  may  be  true  of  the  theobromine  of  the  cocoa-bean. 


CONSTITUENTS   OF   COCOA. 


557 


According  to  A.  H.  Church  {Foods,  page  200),  good  cocoa- 
nibs  contain: — Water,  5'0;  albuminoids,  17'0;  fat,  510;  theo- 
bromine, 1'5  ;  cocoa-red,  3*0  ;  gum,  &c.,  10*9  ;  cellulose  and  lignose, 
8"0  ;  and  mineral  matter,  3  "6  per  cent. 

J.  Bell  gives  the  following  as  the  composition  of  raw  Trinidad 
cocoa-nibs: — Moisture,  5'23;  fat,  50"44 ;  starch,  4*20;  alkaloids, 
0*84 ;  albuminous  matters,  soluble,  6*30,  insoluble,  6*96  ;  astringent 
principle,  6*71;  cocoa-red,  2*20;  gum,  2'17;  cellulose,  6*40;  in- 
definite insoluble  organic  matter,  5*80;  and  ash,  2*75  per  cent. 

The  following  analyses  of  commercial  raw  cocoa,  after  removal 
of  the  husk,  are  by  Eastes  -and  Terry  {Pharm.  Jour.^  [3], 
XV.  764):— 


Kind  of  Cocoa. 

Moisture. 

Fat. 

Theo- 
bromine. 

Ash, 

H3PO4. 

Caraccas, 

4-75 

53-65 

1-08 

2-76 

1-36 

Carupano, 

5-04 

47-38 

0-87 

3-69 

1-39 

Grenada, 

6-59 

47-12 

1-42 

2-81 

0-91 

Guayaquil 

3-68 

52-97 

1-74 

3-28 

0-85 

Para, 

4-39 

57-07 

1-00 

3-09 

1-30 

Surinam, 

2-55 

53-70 

1-42 

2-44 

0-85 

Trinidad  (common),  .      .      .      . 

5-62 

45-71 

105 

2-79 

0-89 

Trinidad  (fine,  St  Antonio),    .       . 

4-72 

53-57 

1-94 

2-70 

1-15 

The  following  analyses  by  C.  Heisch  (Analyst,  i.  142)  show 
the  range  of  variation  of  certain  of  the  constituents  of  commercial 
roasted  cocoa-beans.  The  difference  in  the  proportions  of  husk  is 
due  to  the  great  variation  in  the  thickness  of  the  shells  of  cocoas 
from  different  sources : — 


Kind  of  Cocoa. 

Propor- 
tion of 
Husk. 

Eoasted  Bean  after  Removal  of  Husk, 

ll 

1 

1 

1 

1^ 

Ash. 

Per 
cent. 

H 

II 

i 

JO 

Caraccas, 

18-8 

4-32 

48-4 

1-76 

11-14 

32-19 

3-95 

2-15 

1-54 

Trinidad  (inferior),      . 

15-5 

3-84 

49-4 

1-76 

11-14 

32-82 

2-80 

0-90 

0-98 

Surinam,  .... 

15-5 

3-76 

54-4 

1-76 

1114 

28-35 

2-35 

0-80 

1-23 

Guayaquil,     • 

11-5 

4-14 

49-8 

2  06 

13-03 

30-47 

3-50 

1-75 

1-87 

Grenada 

14-6 

8-90 

45-6 

1-96 

12-40 

85-70 

2-40 

0-60 

1-3.T 

Bahia,      .      .      .      . 

9-6 

4-40 

50-3 

1-17 

7-40 

35-30 

2-60 

0-90 

1-26 

Cuba 

12-0 

3-72 

45-3 

1-37 

8-67 

39-41 

2-90 

0-95 

1-13 

Para, 

8-5 

1 

3-96 

54-0 

2-00 

12-66 

26-33 

805 

1-40 

1-00 

658 


CONSTITUENTS   OF  COCOA. 


J.  Bell  {Analysis  and  AduU&'ation  of  Foods)  gives  the  foUow- 
m(T  particulars  respecting  the  composition  and  the  ash  of  cocoa-nibs 
and  husk : — 


Kind  of  Cocoa. 

Per  100  Parts  of 
Cocoa. 

Per  100  Parts  of  Ash. 

i 

1 
3 

SI 

ii 
1^ 

.s 

P2O6. 

CO2. 

K2O. 

FeO. 

Guayaquil  nibs,  . 

506 

0-54 

3-63 

56-20 

none 

49-39 

0-69 

23-35 

0-21 

Surinam  nibs,      . 

4-55 

0-80 

2-90 

43-45 

none 

37-78  '    3-31 

28-00 

0-38 

Grenada  nibs, 

5-71 

0-91 

2-82 

48-58 

none 

39-20      2-92 

27-64 

0-15 

Finest  Trinidad  nibs.       . 

4-47 

0-84 

2-75 

46-55 

none 

36-20      4-19 

29-30 

0-11 

husks,    . 

10-19 

1-36 

8-63 

54-92 

5-91 

17-17  1 10-80 

37-89 

0-63 

In  these  analyses  the  figures  for  alkaloid  are  probably  considerably 
below  the  truth. 

The  ash  of  cocoa  is  distinguished  by  the  small  proportion  of 
chlorides,  carbonates,  and  sodium  compounds  contained  in  it,  and 
by  the  great  preponderance  (3  or  5  :  1)  of  magnesia  over  lime. 

In  Bell's  analyses  of  cocoa-ash,  no  mention  is  made  of  the 
presence  of  copper.  D  u  c  1  a  u  x  proved  this  metal  to  be  con- 
stantly present  in  cocoa.  Galippe  confirmed  this,  and  found 
proportions  varying  from  0*0112  to  0'0292  grammes  per  kilo- 
gramme of  cocoa.  The  greater  part  of  the  copper  existed  in  the 
husks,  and  in  inferior  kinds  of  chocolate  containing  cocoa-husk 
in  large  proportion  copper  was  occasionally  present  to  the  ex- 
tent of  0*125  gramme  per  kilogramme. 

The  most  important  and  characteristic  constituent  of  cocoa  is 
the  alkaloid  theobromine.  A  small  proportion  of  caffeine  is  some- 
times present  in  addition.  The  recorded  proportions  of  theo- 
bromine are  very  variable  and  generally  untrustworthy.  The 
method  of  determination  has  already  been  described  (page  496). 
P.  Troganowski  {Archiv  der  Pharm.,  [3],  x.  32 ;  Jour.  Chem. 
Soc,  xxxii.  363)  found  from  1*2  to  4*6  per  cent,  of  theobromine  in 
cocoa,  and  concluded,  from  the  result  of  a  large  number  of  experi- 
ments, that  the  proportion  of  alkaloid  does  not  always  bear  a  relation 
to  the  quality  and  value  of  the  cocoa.  This  is  probable,  but  the 
difficulty  attending  the  accurate  determination  of  theo-bromine  in 
cocoa  renders  any  deduction  of  the  kind  of  very  doubtful  value. 

The  fat  of  cocoa  {Oleum  Theobromatis,  B.P.),  sometimes  called 
"cocoa  butter,"    consists    chiefly    of    stearin,    and    is    fully 


CONSTITUENTS   OF   COCOA.  659 

described  on  page  568.  The  proportion  of  fat  present  in  cocoa- 
nibs,  free  from  husk,  varies  only  a  few  units  on  each  side  of  50 
per  cent.,  and  hence  is  valueless  for  the  discrimination  of  samples 
from  different  sources. 

The  taste  and  aroma  of  cocoa  are  chiefly  due  to  a  volatile 
substance,  probably  an  essential  oil,  which  a]ipears  to  be  developed 
by  roasting,  in  the  same  manner  as  the  caffeol  of  coffee  (page  532). 
The  tannin  of  cocoa  also  contributes  to  the  flavour. 

The  cocoa-red  probably  does  not  pre-exist  in  cocoa,  but  is  a 
product  of  the  oxidation  of  the  tannin.  If  cocoa,  from  which  the 
fat  has  been  previously  removed  (by  petroleum  spirit),  be  ex- 
hausted with  alcohol,  and  the  solution  treated  with  acetate  of  lead, 
a  precipitate  is  produced,  which,  when  suspended  in  water  and 
decomposed  by  sulphuretted  hydrogen,  yields  a  clear  and  colourless 
filtrate ;  but  on  evaporating  this  liquid,  it  acquires  a  bright  red 
colour,  and  on  taking  up  the  residue  with  water,  cocoa-red  remains 
insoluble.  Cocoa-red  gives  various  coloured  precipitates  with 
metallic  salts,  the  tints  depending  on  the  extent  to  which  oxida- 
tion has  occurred,  and,  apparently,  on  thf»  variety  of  cocoa  employed. 
P.  Troganowski  {Archiv.  der  Phari.c,  [3],  x.  32  ;  Jour.  Ghem. 
Sac,  xxxii.  363)  has  described  various  colour-reactions  yielded  by 
the  aqueous  or  alcoholic  solutions  of  cocoa  from  various  sources, 
but  the  value  of  the  indications  obtained  is  very  questionable. 

The  gum  of  cocoa  closely  resembles  gum-arabic  in  appearance, 
and  yields  mucic  acid  on  oxidation  with  nitric  acid.  It  differs 
from  gum-arabic  in  being  strongly  dextro-iotatoTj . 

The  starch  of  cocoa  is  present  in  only  moderate  proportion,  and 
the  amounts  recorded  by  some  observers  are  probably  in  excess  of 
the  truth.  The  granules  are  small,  round,  and  exhibit  a  central 
hilum.  Under  the  microscope  they  are  readily  distinguished 
from  the  granules  of  added  starches. 

Nitrogenous  constituents  of  cocoa.  G.  W.  Wigner  (1878) 
showed  that  of  the  nitrogen  of  cocoa  only  a  portion  varying  from 
39  to  78  per  cent,  existed  in  a  coagulable  form  (Analyst,  iv.  8). 
The  total  nitrogen,  as  determined  by  combustion  with  soda-lime, 
ranged  from  0'70  to  2'98  per  cent.,  and  that  existing  as  coagulable 
albuminoids  from  0*33  to  2*33  per  cent.  According  to  Wigner, 
of  the  nitrogen  in  a  non-coagulable  form,  part  exists  as  theobromine 
and  a  further  portion  as  nitrates.  Wigner  argued  from  this  that 
the  value  of  cocoa  as  food  had  been  over-estimated. 

Weigmann  similarly  found  only  42  per  cent,  of  the  nitro- 
genous substances  in  cocoa  to  be  digestible  ;  and  S  t  u  t  z  e  r  states 
that,  in  spite  of  apparently  favourable  conditions,  due  to  the 
physical  condition  of  commercial  cocoa,  a  large  proportion  of  the 


560 


MANUFACTURED   COCOAS. 


nitrogenous  constituents  remains  entirely  indigestible.  S  t  u  t  z  e  i 
classifies  the  nitrogenised  compounds  of  cocoa  as  follows : — 1. 
Non-proteids  ;  substances  soluble  in  neutral  aqueous  solution  in 
presence  of  cupric  hydroxide  (theobromine,  ammonia,  amido-com- 
pounds).  2.  Digestible  albumin;  insoluble  in  neutral  aqueous 
solutions  in  presence  of  cupric  hydroxide,  but  soluble  when  treated 
successively  with  acid  gastric  juice  and  alkaline  pancreas  extract. 
3.  Insoluble  and  indigestible  nitrogenous  substances. 

The  following  are  the  results  of  the  analysis  of  four  cocoa 
powders  examined  by  S  t  u  t  z  e  t  (Zeitsch.  f.  angeio.  Chem.,  1891, 
page  368)  for  the  purpose  of  determining  the  effect  of  the  process 
of  manufacture  on  the  chemical  constituents.  A  was  composed 
of  40  per  cent.  Ariba,  40  of  Machala,  and  20  of  Bahia  cocoa,  and 
was  manufactured  by  Wittekop  &  Co.  without  the  use  of  chemicals. 
B  is  a  sample  of  a  well-known  cocoa  manufactured  in  Holland 
with  the  addition  of  potash.^  C  and  D  are  German  cocoas,  and, 
in  Stutzer's  opinion,  were  prepared  by  the  use  of  ammonia  : — 


A. 


D. 


Water, 

Fibre, 

Nitrogen-free  extract,       .... 
Total  nitrogenous  substances,!^ 

Tat 

Ash,2 

1  Containing  total  nitrogen,       .... 

Composed  of  :— 

Theobromine 

Ammonia, 

A.mido-compounds, 

Digestible  albumin, 

Indigestible  nitrogenous  substances,    . 

Containing  nitrogen,  . 

Proportion   of    total   nitrogen   indi-\ 
gestible, / 

a  Containing :  -Total  P2O6 

P2O5  soluble  in  water,    . 
Ratio  of  total  P2O5  to  soluble. 
Ash  soluble  in  water. 
Ratio  of  total  ash  to  soluble. 


Per  cent. 
4-30 


20-84 

27-83 

5-05 


Per  cent. 
3-83 

37-48 

19 '88 

30-51 

8-30 


Per  cent. 
6-56 

39-99 

20-93 

27-34 

5  18 


Per  cent. 
5-41 

36-06 

19-25 

83-85 

5-43 


100-00 


100-00 


100-00 


100-00 


3-68 

1-92 
0-06 
1-43 
10-25 
7-18 
1-15 

31-2 


3-30 

3-95 

1-73 

1-98 

0-03 

0-46 

1-25 

0-31 

7-68 

10-50 

9-19 

7-68 

1-47 

1-23 

14-5 

31-2 

3-57 

1-80 
0-33 
1-31 

7-81 
8-00 
1-28 

85-8 


1-85 
1-43 

100:77 
3-76 

100  :  74 


2-52 
0-50 

100:19 
4-76 

100:57 


2-14 
0-74 

100 :  34 
2-82 

100 :  54 


2-05 
0-77 

100 :  37 
2-76 

100 :  49 


^An   analysis  of  the   ash   of  Van   Houten's  cocoa  by  Konig  (in  1880) 
showed:— Total  ash,  7'84;  KgO,   3-52  ;  CaO,  0-27  ;  MgO,   0-81  ;  PA.  1"84 


COMMERCIAL  COCOA.  561 

Commercial  Cocoa  and  Chocolate. 

In  its  simplest  form,  commercial  cocoa  consists  of  the  roasted 
and  husked  seeds  ("  nibs ")  ground  to  a  paste  or  semi-fluid,  and 
run  into  the  form  of  cakes.  Flake  cocoa  is  sometimes  made  by 
passing  the  decorticated  seeds  through  a  particular  kind  of  rollers ; 
but  it  is  mostly  made  from  the  small  particles  containing  much 
shell  and  germ,  separated  by  the  sieves. 

The  term  "cocoa"  is  sometimes  misapplied  to  mixtures  of  real 
cocoa  with  sugar,  &c.  The  practice  is  highly  objectionable  and  has 
led  to  much  confusion.  It  is  better  to  describe  all  such  cocoa  mix- 
tures as  chocolate,  reserving  the  name  cocoa  for  the  unmixed  article. 

All  good  cocoa  preparations  should  be  made  from  the  cotyledons 
only,  though  the  husks  enter  into  the  composition  of  many  of  the 
inferior  kinds  of  cocoa  and  chocolate.  In  Germany,  under  the 
name  of  "cocoa-tea,"  and  in  Ireland  as  " miserables,"  cocoa- 
husks  are  an  independent  article  of  commerce,^  the  infusion  of 
which  in  boiling  water  is  drunk  after  the  manner  of  tea. 

The  large  proportion  of  fat  in  cocoa  (averaging  50  per  cent.) 
renders  it  impossible  to  manufacture  a  permanent  preparation  in 
the  form  of  powder,  without  either  removing  a  portion  of  the  fat 
or  diluting  the  material  with  some  non-fatty  matter,  such  as  sugar, 
starch,  or  farina.  Hence,  there  are  two  distinct  types  of  "cocoa" 
known  in  commerce,  namely  : — 

"l.  Preparations  commonly  called  "coco  a-e  s  s  e  n  c  e,"  or 
"cocoa-extrac t,"  consisting  of  ground  cocoa-nibs,  from  which 
a  part  of  the  fat  has  been  removed  by  heat  and  pressure. 

2.  Preparations  to  which  sugar  and,  generally,  some  starchy 
material  have  been  added.  The  sugar  is  usually  sucrose  (cane  or 
beet  sugar),  but  reducing  sugars  are  sometimes  present  in  notable 
quantity.  Of  the  pure  starches,  arrowroot  and  rice  starch  are  used 
in  the  better  preparations,  while  wheat-  and  potato-starches  and 
wheat-flour  are  also  met  with.  Moeller  also  mentions  acorn 
and  rye  flours,  ground  earth-nuts,  and  malt,  to  which  M  a  c  ^  adds 
almond-cake  and  sawdust.  Any  cheap  vegetable  material,  capable 
of  being  reduced  to  fine  powder,  is  liable  to  be  used  by  unscrupulous 

per  cent.  Belohubeck(in  1888)  found  :  —Total  ash,  7 '88  ;  and  for  100  of 
total  ash,  KgO,  52*89 ;  CaO,  1  '56 ;  MgO,  10-45 ;  P2O5,  24*91  ;  CO2,  3*45  per  cent. 
^  In  large  cocoa  manufactories  the  husks  are  sorted  by  sieves  into  several 
sizes.  The  largest  are  employed  for  infusion,  and  the  finest,  containing  a  con- 
siderable admixture  of  the  kernels,  are  ground  up  with  sugar  and  cacao-butter 
to  produce  a  low  grade  of  chocolate.  The  intermediate  sizes  are  not  readily 
applicable  for  either  of  the  above  purposes,  and  hence  fetch  a  lower  price  than 
the  coarsest  and  finest  husks.  They  are  employed  for  cattle-food,  and  at 
Hamburg  are  pressed  for  the  extraction  of  cacao-butter. 

VOL.  III.  PART  II.  .  2  K 


562 


COCOA  ESSENCE. 


cocoa  manufacturers,  but  the  better  class  of  preparations  which 
have  acquired  a  reputation  in  the  United  Kingdom  are  free  from 
any  suspicion  of  such  admixtures. 

A  considerable  addition  of  cacao-butter  is  made  to  some  kinds 
of  chocolate.^ 

The  flavouring  agents  added  to  chocolate  are  most  frequently 
vanilla  and  cinnamon.  Artificial  vanillin,  nutmeg,  cloves,  mace, 
&c.,  are  also  used.  In  addition  to  the  mechanical  difficulty  of 
manipulating  undiluted  cocoa  containing  all  its  natural  fat,  it  is 
stated,  with  some  probability,  that  the  excessive  proportion  of  fat 
renders  the  cocoa  difficult  of  digestion.  Hence  the  removal  of  a 
portion  of  the  fat,  and  consequent  concentration  of  the  non-fatty 
constituents  of  the  cocoa,  appears  to  be  distinctly  advantageous. 

A  further  treatment  of  the  concentrated  cocoa  is  practised  by 
some  manufacturers  of  cocoa-essence,  especially  by  Dutch  firms. 
This  treatment  consists  in  the  addition  to  the  cocoa  of  an  alkali, 
which  may  be  either  ammonia  or  a  fixed  alkali  or  alkaline  car- 
bonate, whereby  the  fat  becomes  emulsified  and  any  free  fatty  acids 
saponified.  Hence,  on  subsequently  treating  the  cocoa  with  hot 
water  there  is  less  tendency  to  the  separation  of  oily  globules. 
The  effect  on  the  composition  of  the  cocoa  is  shown  in  the  results 
of  Stutzer  on  page  560,  from  which  it  appears  that  the  fact  of  the 
treatment  can  be  readily  detected.  In  the  case  of  a  well-known  brand 
of  cocoa,  potassium  carbonate  is  used.  In  another  case,  the  cocoa- 
beans  are  soaked  in  water  containing  from  2  to  4  per  cent,  of  their 
weight  of  caustic  potash  or  soda. 

The  following  figures  were  obtained  by  the  analysis,  in  the 
author's  laboratory,  of  a  specimen  of  the  best  cocoa-nibs  and  two 
of  the  leading  brands  of  cocoa-essence  or  soluble  cocoa,  to  which 
no  starch  or  sugar  had  been  added : — 


Cocoa- 

Sample 

Sample 

nibs. 

A. 

B. 

Per  cent. 

Per  cent. 

Per  cent. 

ash:- 

2-53 

4-93 

8-25 

Insoluble  in  water, 

1-71 

3*50 

2-09 

Soluble  in  water, 

0-82 

1-43 

6-16 

Alkalinity  (KgO)  of  soluble  portion,  .      .      .      . 
Cold  Water  Extract  :— 

0-32 
9-72 

0-49 
11-64 

3-23 
18-66 

Alkalinity  (K2O)  to  methyl-orange,    .      .      .       . 
Acidity  (K2O)  to  phenolphthalein,     .      .      .      . 

0-69 

0-71 

202 

0-63 

0-76 

0-38 

Hot  Water  Extract  :— 

16-84 

20-36 

27-16 

Containing :— Ash, 

3-34 

4-93 

7-85 

Organic  extract, 

13-50 

15-43 

19-31 

^"Chocolate  creams"  consist  of  a  core  or  kernel  of  pure  sugar, 
enveloped  in  a  mixture  of  ground  cocoa,  cacao-butter,  sugar,  and  flavouring 
materials. 


COMMERCIAL  COCOAS. 


563 


The  curious  property  possessed  by  the  cold-water  extract  of  being 
at  once  alkaline  to  methyl-orange  and  acid  to  phenolphthalem 
indicates  the  presence  of  a  soluble  salt  of  some  weak  organic  acid, 
together  with  a  small  proportion  of  free  organic  acid.  The  treat- 
ment with  alkali  which  sample  B  had  received  appears  to  have 
notably  increased  the  proportion  of  matter  actually  soluble  in  water. 

The  misuse  of  the  term  "soluble"  by  cocoa  manufacturers  is 
notorious;  the  real  object  sought,  and  to  some  extent  attained, 
being  the  formation  of  an  emulsion  which  is  readily  miscible  with 
hot  water.  This  desideratum  is  the  more  important  owing  to  the 
difficult  digestibility  of  some  of  the  nitrogenous  constituents  of 
cocoa  (see  page  559). 

The  following  results,  among  many  others,  were  obtained  by  E.  E. 
E  well  {Bulletin  No.  13,  U.S.  Department  of  Agriculture)  by  the 
analysis  of  well-known  brands  of  commercial  cocoa  and  its  pre- 
parations : — 


Description  of  Sample. 

^ 

S 

i 

1 

CO 

s 

1 

h 

S  be 

1- 

Ash. 

Added  Starch. 

Total. 

Acid- 
equiva- 
lent.2 

Fry's  Cocoa  Extract    . 

1 

30-95 

3-89 

... 

... 

4-21 

5-8 

None. 

Schweitzer's  Cocoatina, 

1 

31-13 

3-70 

... 

... 

6-33 

9-4 

None. 

Van  Houten's  Cocoa,  . 

1 

29-Sl 

4-33 

... 

... 

8-64 

1605 

None. 

Blooker's  Dutch  Cocoa, 

0 

31-48 

3-76 

... 

6-06 

9-6 

None. 

Rowntree's    Extract  \ 
of  Cocoa,     .       .      / 

2 

27-56 

4-42 

... 

8-48 

16-6 

None. 

Rowntree's  Powdered  I 
Chocolate,  .      .     / 

2 

25-84 

1-30 

61 

none 

1-66 

2-25 

(  Very  small  amount 
(     of  arrowroot. 

Epps'  Prepared  Cocoa, 

... 

25-94 

1-61 

26 

none 

8-15 

2-6 

Much  arrowroot. 

Fry's  Diamond  Sweet  \ 
Chocolate,  .      .      / 

2 

18-60 

-81 

55 

some 

1-16 

1-45 

(Much  wheat-starch 
■I  with  some  arrow- 
(    root. 

London    Cocoa   (un-\ 
known  maker),  .      / 

3 

11-13 

2-13 

32 

some 

2-82 

8-9 

/Very  largely  diluted 
\     with  arrowroot. 

Chocolat-Menier, 

0 

21-31 

1-10 

58 

none 

1-40 

2-05 

None. 

1  In  the  column  headed  "  husk,"  0  signifies  that  no  characteristic  husk-tissue  could  be 
found  under  the  microscope;  1  signifies  that  the  husk  had  probably  been  mostly  removed  ; 
2  signifies  that  the  husk  had  probably  been  partly  removed ;  and  3  that  the  husk  was  prob- 
ably all  present.  But  Ewell's  observations  with  respect  to  the  husk  of  commercial  cocoas 
are  not  in  all  cases  borne  out  by  the  examination  of  other  samples  of  the  same  prepara- 
tions, and  must  be  received  with  caution. 

2  The  figures  in  the  column  headed  "acid-equivalent"  represent  the  number  of  c.c.  of 
decinormal  acid  required  to  neutralise  the  ash  from  2  grammes  of  the  sample.  It  is  a 
rough  measure  of  the  fixed  alkali  used  in  the  manufacture. 


564 


COMMERCIAL  COCOAS. 


Owing  to  a  considerable  proportion  of  the  natural  fat  having 
frequently  been  removed,  the  proportion  of  real  cocoa  in  a  mixture 
cannot  be  assumed  to  be  approximately  double  the  percentage  of 
fat.  A  better  idea  of  the  proportion  of  the  additions  is  obtained 
by  stating  the  fat  and  non-fatty  constituents  separately.  This 
plan  is  adopted  by  J.  Bell,  and  is  shown  in  the  following  analyses 
by  him,  representing  the  composition  of  certain  commercial  pre- 
parations of  cocoa : — 


Description. 

Moisture. 

Fat. 

Added 
Sugar. 

Added 
Starch. 

Non-fatty 
Cocoa 

G)y  differ- 
ence). 

Nitrogen. 

Finest  Trinidad  nibs,  . 

2-60 

51-77 

none 

none 

45-63 

2-95 

Cocoa  Extract,      . 

5-76 

29-50 

none 

none 

64-74 

Not  determined. 

Flake  Cocoa,  . 

5-49 

28-24 

none 

none 

66-27 

3-06 

Gocoatina, 

3-62 

23-98 

none 

none 

72-50 

4-07 

Chocolatine,   . 

4-40 

29-60 

none 

none 

66-00 

4-36 

Chocolat  de  Sant^, 

1-44 

22-08 

61-21 

2-00 

13-27 

Not  determined. 

Prepared  Cocoa,    . 

4-95 

24-94 

23  03 

1919 

27-89 

2-24 

Iceland  Moss  Cocoa,    . 

5-47 

16-86 

29-23 

24-70 

23-74 

1-38 

Rock  Cocoa,    . 

2-58 

22-76 

32-20 

17-56 

24-90 

Not  determined. 

According  to  evidence  given  in  the  case  of  G  i  b  s  o  n  v.  L  e  a  p  e  r, 
"  Epps'  cocoa  "  contains  40  per  cent,  of  cocoa,  1 6  of  starch  (West 
Indian  arrowroot),  and  44  per  cent,  of  sugar.  "  Granulated  cocoa  " 
is  chiefly  a  mixture  of  cocoa-nibs,  sugar,  and  arrowroot ;  while  in 
"Maravilla  cocoa"  the  arrowroot  is  replaced  by  sago.  Bernhardt 
states  that  he  has  met  with  chocolates  consisting  of  cocoa-remnants, 
fat,  sugar,  spices  and  colouring  matter,  and  containing  no  true  cocoa 
whatever.  The  cocoa-butter  is  said  to  be  liable  to  be  replaced 
by  cheaper  fats,  and  vanilla  and  vanillin  by  Peruvian  or  Tolu 
balsam,  storax,  or  gum  benzoin. 

Analysis  of  Commercial  Cocoa  and  Chocolate. 

The  complete  analysis  of  cocoa  is  rarely  required.  A  careful 
microscopic  examination  will  indicate  the  presence,  and  in  many 
cases  the  nature,  of  most  foreign  additions,  and  prove  the  presence 
of  husk -structure.  The  various  starches  may  also  be  identified 
by  the  microscope.  The  proportion  of  fat  affords  further  informa- 
tion, and  the  percentages  of  sugar  and  starch  complete  what 
is  usually  required,  unless  it  is  desired  to  ascertain  the  nature 
and  amount  of  the  alkali  added.  The  following  scheme  of 
analysis  will  allow  of  the  above  information  being  obtained  : — 


ANALYSIS  OF  COCOA   MIXTURES.  565 

Ignite  5  grammes  of  the  sample,  weigh  the  ash  and  treat  with 
hoihng  water.  Wash,  dry,  ignite,  and  weigh  the  insoluble  portion. 
Titrate  the  filtrate  with  decinormal  acid  to  determine  the  alJialinity, 
which  will  be  excessive  where  the  cocoa  has  been  prepared 
with  a  fixed  alkali.  The  addition  to  cocoa  of  ferruginous 
pigments,  such  as  rouge,  ochre,  and  venetian-red,  was  formerly 
practised,  and  the  author  was  recently  consulted  as  to  the  probable 
legal  consequences  of  their  use.  He  has  also  examined  a  pre- 
paration consisting  essentially  of  oxide  of  iron,  which  has  recently 
been  offered  to  cocoa-manufacturers.  Where  the  proportion  of  the 
diluents  is  large,  the  importance  of  deepening  the  colour  of  the 
mixture  is  considerable.  The  addition  of  ferruginous  matters  would 
be  readily  detected  by  the  excessive  proportion  of  the  ash,  which 
in  the  case  of  genuine  cocoa  is  white,  and  very  rarely  in  excess  of 
4  per  cent,  (in  the  absence  of  husk  and  added  alkalies,  and  when 
the  fat  has  not  been  removed).  The  proportion  of  oxide  of  iron 
in  cocoa  is  very  trifling,  ranging  from  0*10  to  0'38  per  cent,  of 
the  ash,  while  even  in  the  husk  it  only  amounts  to  0"63  per  cent. 
of  the  ash. 

Dry  5  grammes  of  the  sample  in  the  water-oven  at  100°  C.  and 
note  the  loss  of  weight,  which  represents  moisture.  Boil  the  dried 
substance,  reduced  to  powder  if  necessary  and  preferably  mixed 
with  a  known  weight  of  dry  sand,  with  redistilled  petroleum 
spirit.  Pour  off  the  solution,  and  repeat  the  treatment  till  the 
fat  is  entirely  removed.  Wash  the  residue,  dry  it  in  the  bath  and 
re  weigh.  The  loss  represents  fat,  with  a  near  approach  to  accuracy. 
A  direct  determination  may  be  obtained  by  evaporating  the  petroleum 
spirit,  and  the  physical  and  chemical  characters  of  the  residual  fat 
can  then  be  ascertained.^ 

The  residue  left  after  the  extraction  of  the  fat  is  exhausted  with 
hot  spirit  of  0"850  specific  gravity,  which  dissolves  sugar,  tartaric 
acid,  tannin,  soap,  theobromine,  &c.  Ihe  hot  solution  is  treated 
with  lead  acetate  and  filtered  from  the  precipitate  of  lead  tartrate^ 
tannate,  stearate,  &c.  From  the  concentrated  filtrate  the  theo- 
hromine  can  be  extracted  by  agitation  with  warm  chloroform,  but 
where  the  determination  is  not  required  this  stage  of  the  process 
may  be  omitted.  The  aqueous  liquid  is  freed  from  traces  of  chloro- 
form by  boiling  or  agitation  with  petroleum  spirit,  and  after  removal 

^  Cocoa  which  has  been  treated  with  an  alkali  contains  a  notable  quantity 
of  soap,  which  is  not  dissolved  by  the  petroleum  ether.  It  is  best  extracted 
by  treating  the  residue  with  alcohol  containing  a  few  drops  of  hydrochloric 
acid,  evaporating  the  alcoholic  solution,  and  shaking  the  residual  liquid  with 
water  and  ether.  On  separating  and  evaporating  the  ethereal  layer,  the  fatty 
acids  of  the  soap  will  be  left. 


566  SUGAR   IN   COCOA. 

of  the  excess  of  lead  by  sodium  phosphate  is  fit  for  determination 
of  the  sugar.  This  may  be  effected  by  inversion  and  treatment  with 
Fehling's  solution,  or  by  means  of  the  polari meter.  The  difference 
in  the  amount  of  sugar  found  before  and  after  inversion  represents 
the  cane-sugar  added.  The  alcoholic  extract  of  genuine  cocoa,  after 
treatment  with  lead  acetate,,  does  not  sensibly  reduce  Fehling's 
solution,  so  that  any  precipitate  yielded  before  inversion  represents 
glucose^  introduced  as  such  or  present  in  the  cane-sugar  added.^ 

The  residue  left  after  treatment  with  alcohol  contains  gum, 
starch,  cellulose,  fibre,  albuminoid  matters,  &c.  After  weighing, 
an  aliquot  part  may,  if  desired,  be  used  for  the  determination  of 
the  contained  nitrogen  by  Kjeldahl's  process  or  combustion  with 
soda-lime,  and  the  amount  found  calculated  to  albuminoids  by 
multiplying  by  6-25.  The  residue  may  also  be  advantageously 
examined  under  the  microscope  at  this  stage,  since  by  the  removal 
of  the  oil,  sugar,  and  colouring  matters  the  starch  and  woody 
structure  are  seen  to  great  advantage.  On  the  presence  or  absence 
of  foreign  starch  will  usually  depend  the  necessity  of  performing 
the  subsequent  operations  for  its  quantitative  determination. 

For  the  determination  of  starchy  an  aliquot  part  of  the  residue 
from  the  alcohol  treatment  2  should  be  heated,  under  a  pressure  of 

^  A  determination  of  the  amount  of  sugar  added  to  cocoa  can  be  readily 
effected  to  within  2  per  cent,  of  the  truth,  but  a  strictly  accurate  estimation 
is  not  required,  and  would  be  very  difficult.  The  sugar  can  be  determined  in 
the  aqueous  instead  of  the  alcoholic  extract  of  the  cocoa,  but  in  that  case  the 
solution  contains  the  natural  gum,  which  has  a  dextro-rotatory  power  equiva- 
lent to  0*3  to  2*0  per  cent,  of  cane-sugar  in  the  somple,  and  a  large  volume  of 
cold  water  must  be  used  for  the  extraction.  E.  E.  E  w  e  1 1  {Bulletin  No.  13, 
U.S.  Department  of  Agriculture)  recommends  the  following  method  for  the 
polarimetric  determination  of  sugar  in  the  aqueous  extract  of  cocoa  :— 13'024 
grammes  weight  of  the  material  is  triturated  in  a  small  mortar  with  alcohol 
until  a  smooth  paste  is  obtained.  This  is  transferred  to  a  500  c.c.  flask, 
diluted  with  about  400  c.c.  of  water,  and  the  liquid  shaken  occasionally  for 
three  or  four  hours,  when  10  c.c.  of  a  saturated  solution  of  neutral  lead  acetate 
should  be  added  and  the  volume  brought  to  500  c.c.  After  standing  for  an 
hour  with  occasional  agitation,  the  solution  is  filtered  and  polarised  in  a  4 
decimetre  tube  (twice  the  usual  length).  If  the  instrument  be  one  intended 
for  use  with  26*048  grammes  of  sugar,  the  percentage  of  cane-sngar  in  the 
sample  will  be  found  by  the  following  formula,  in  which  R  is  the  reading  in 
sugar-units  : — 

^  frnn     no.no^x     RRxl3-024-l  ^      „ 

Tqq    500-(13"024) — — =percent.  of  sucrose. 

'  The  residue  is  preferably  first  treated  with  cold  water,  to  dissolve  gummy 
matters,  but  except  in  cases  where  great  accuracy  is  required  this  part  of  the 
process  may  be  omitted. 


STARCH  IN  COCOA.  567 

1  atmosphere,  for  one  hour  with  50  c.c.  of  water  and  1  c.c.  of 
fuming  hydrochloric  acid.^  This  treatment  effects  the  complete 
conversion  of  the  starch  into  maltose  and  dextrin,  and  the  further 
change  of  these  to  dextrose,  without  appreciahly  affecting  the 
cellulose.  The  solution  is  filtered  from  the  insoluble  matter,  fibre 
(sand),  &c.,  and  the  dextrose  determined  in  the  neutralised  filtrate 
by  Fehling's  solution.  Ten  parts  of  dextrose  found  represent  9 
of  starch  in  the  sample. 

The  mixed  cellulose,  fibres  and  sand,  left  after  the  conversion  of 
the  starch  by  hydrochloric  acid,  should  be  treated  with  a  solution 
of  2  per  cent,  caustic  soda  to  remove  nitrogenous  matters,  washed 
successively  with  very  dilute  hydrochloric  acid,  alcohol  and  ether, 
dried  and  weighed.^ 

An  alternative  method  of  estimating  starch  consists  in  treating 
the  fat-free  cocoa  with  cold  water,  to  remove  all  sugar,  gum,  &c. 
The  liquid  is  filtered  and  the  residue  washed  with  decinornml 
caustic  soda  (4  grammes  ISTaHO  per  litre)  to  remove  albuminoids. 
The  residue  is  rinsed  off  the  filter  with  warm  water,  the  liquid 
heated  to  boiling  while  constantly  stirred,  so  as  to  gelatinise  the 
starch,  and  the  product  treated  with  a  known  measure  of  recently- 
prepared  and  filtered  cold  aqueous  infusion  of  malt,  of  which  the 
specific  gravity  has  been  previously  ascertained.  The  mixture  is 
kept  at  a  temperature  of  60°  to  63°,  with  occasional  stirring,  until 
a  drop  taken  out  with  a  glass  rod  and  added  to  a  drop  of  dilute 
iodine  solution  on  a  porcelain  plate  shows  no  blue  or  brown  colora- 
tion.    The  solution  is  then  filtered,  made  up  to  a  definite  volume, 

^  A  simple  and  convenient  apparatus  for  effecting  the  conversion  consists  of 
a  soda-water  bottle  fitted  with  an  india-rubber  stopper,  through  which  passes 
a  long  glass  tube  bent  twice  at  right  angles  and  immersed  to  a  depth  of  30 
inches  in  mercury  contained  in  a  long  vertical  glass  tube  or  piece  of  narrow 
(iron)  gas-pipe.  The  stopper  should  be  carefully  secured  by  wire.  The  soda- 
water  bottle  may  be  heated  in  a  bath  of  paraffin  or  oil,  or  in  a  boiling 
saturated  aqueous  solution  of  sodium  nitrate.  This  last  liquid  has  a  tem- 
perature of  121°  C,  corresponding  to  one  additional  atmosphere  of  pressure, 
so  that  no  regulation  is  required,  and  if  preferred  the  exit-tube  may  be  dis- 
pensed with  and  the  cork  or  stopper  firmly  secured  in  position. 

*  For  the  direct  determination  of  the  crude  fibre,  2  grammes  of  the  sample 
of  cocoa  should  be  freed  from  fat  and  boiled  for  half  an  hour  under  a  reflux 
condenser  with  200  c.c.  of  water  and  1\  c.c.  of  sulphuric  acid.  The  liquid  is 
filtered  through  linen  and  the  residue  thoroughly  washed  with  hot  water  and 
then  boiled  with  200  c.c.  of  1 J  per  cent,  caustic  soda.  The  residue  is  filtered 
off,  washed  in  succession  with  hot  water,  alcohol,  and  ether,  dried  at  110°,  and 
weighed.  It  is  then  ignited,  and  the  loss  regarded  as  crude  fibre.  In  cocoa 
free  from  husk  it  will  amount  to  2  or  3  per  cent,  only,  but  will  exceed  this 
limit  in  proportion  to  the  amount  of  husk  present. 


668  ANALYSIS   OF   COCOA. 

and  its  specific  gravity  accurately  ascertained.  From  the  excess 
of  the  density  over  water  is  subtracted  the  density  due  to  the 
infusion  of  malt  used,  allowance  being  made  for  the  increased 
volume  of  the  liquid,  when  the  difference  represents  the  density 
due  to  the  starch  dissolved,  and  this  number  divided  by  4*096 
(  =  3'95,  the  density-coefficient  of  a  solution  of  mixed  maltose  and 
dextrin,  multiplied  by  1*037,  the  yield  of  these  from  1  part  of 
starch)  gives  the  number  of  grammes  of  starch  in  each  100  c.c.  of 
the  solution.^ 

The  total  nitrogen  of  cocoa  can  be  determined  on  2  to  3 
grammes  by  Kjeldahl's  method,  or  by  combustion  with  soda-lime. 
The  assumption  that  the  proportion  of  albuminoids  can  be  found 
by  multiplying  the  nitrogen  by  6*25  leads  to  an  estimate  greatly  in 
excess  of  the  truth.  The  theobromine  of  cocoa  contains  31*1  per 
cent,  of  nitrogen,  or  nearly  twice  as  much  as  albumin.  Hence  to 
obtain  an  estimate  of  proteids  from  the  nitrogen  of  the  sample, 
the  proportion  of  that  element  corresponding  to  the  theobromine 
present  must  first  be  deducted.  But  as  the  determination  of 
theobromine  is  somewhat  troublesome,  it  is  preferable  to  operate 
on  a  cocoa-residue  which  has  been  already  exhausted  with  petroleum 
spirit,  alcohol,  and  amylic  alcohol  or  chloroform,  so  as  to  eliminate 
with  certainty  the  whole  of  the  theobromine. 

Cacao-butter  {Oleum  Theohromatis)  is  the  fat  contained  in  cocoa- 
beans,  and  must  not  be  confused  with  cocoa-nut  oil  from  Cocos 
nucifera. 

Cacao-butter  is  expressed  from  cocoa  in  the  process  of  manu- 
facture, and  by  far  the  larger  quantity  used  in  the  United  Kingdom 
is  the  produce  of  one  firm.  It  is  used  in  pharmacy ;  for  the  pro- 
duction of  some  kinds  of  chocolate ;  and  in  the  manufacture  of 
high-class  soap.  Cacao-butter  is  liable  to  adulteration  with  or 
substitution  by  other  fats,  and  it  is  said  that  the  cacao-butter  is 
sometimes  very  completely  expressed  from  cocoa  and  replaced  by 
tallow,  cocoa-nut  oil,  or  other  comparatively  cheap  fat. 

A  careful  observation  of  the  physical  and  chemical  characters  of 

^  Thus,  suppose  20  grammes  of  the  sample  of  cocoa  be  taken,  and,  after 
extraction  of  the  fat  and  treatment  with  cold  water  and  soda  in  the  manner 
described,  the  residue  be  treated  with  50  c.c.  of  water  and  5  c.c.  of  infusion  of 
malt  of  1060  specific  gravity  ;  the  liquid  being  subsequently  made  up  to 
100  c.c.  and  found  to  have  a  density  of  1023.     Then  the  correction  due  to  the 

malt-extract  will  be  "lOO^^  "°^  '  ^"^  *^^^  ^^ure,  subtracted  from  the 

density  of  the  solution  less  that  of  water  (1023-1000  =  23),  leaves  20  as  the 
excess-density  caused  by  the  solution  of  the  starch  of  the  sample  ;  and  this 
figure  divided  by  4*096  gives  4-9  grammes  per  100  c.c.  or  in  the  20  grammes 
taken  ;  or  24-5  per  cent,  of  starch  in  the  sample. 


CACAO-BUTTER. 


569 


cacao-butter  will  allow  of  the  detection  of  other  fats,  if  present  in 
any  considerable  proportion. 

Pure  cacao-butter  is  a  yellowish  fat,  gradually  becoming  paler  on 
keeping.^  At  the  ordinary  temperature  it  may  be  broken  into  frag- 
ments, but  softens  in  the  hand  and  melts  in  the  mouth.  Cacao- 
butter  has  an  agreeable  odour,  tastes  like  chocolate,  and  does  not 
readily  become  rancid.  It  dissolves  in  20  parts  of  hot  alcohol, 
separating  almost  completely  on  cooling,  and  is  also  soluble  in  ether, 
acetic  ether,  &c. 

Cacao-butter  owes  its  value  for  the  production  of  pessaries  and 
suppositories  to  the  fact  of  its  having  a  melting-point  slightly 
below  the  temperature  of  the  human  body  (98°  F.  =  36'6°  C). 
According  to  most  observers,  it  fuses  between  30°  and  33°  C. 
(rarely  at  26°)  to  a  transparent  yellowish  liquid,  which  congeals 
again  at  20°— 21°,  the  temperature  rising  to  about  27°  C. 
According  to  the  British  Pharmacopoeia,  the  melting-point  of 
cacao-butter  ranges  between  30°  and  35°  C.  (86°-95°  F.).^ 

^  It  is  to  be  regretted  that  the  yellowish  tint  of  cacao-butter  is  not  more 
generally  recognised  as  a  natural  characteristic.  It  is  probable  that  the 
quality  of  cacao-butter  is  necessarily  affected  for  the  worse  by  any  process  of 
decolorisation. 

2  R.  Benseraaun  {Zeit.  Anal.  Chem.,  xxiv.  628  ;  Joicr.  Soc.  Chem.  Ind., 
iv.  535)  has  observed  the  melting-point  of  cacao-butter  and  the  fatty  acids 
resulting  from  its  saponification,  and  finds  the  figures  for  the  latter  remark- 
ably constant.  He  places  a  drop  of  the  previously-melted  fat  or  fatty  acid  in 
the  wider  part  of  a  piece  of  quill-tubing  drawn  out  to  a  capillary  form  and 
closed  at  one  end.  The  substance  is  allowed  to  solidify  completely,  and  the 
tube  is  then  attached  to  a  thermometer  and  placed  in  water,  which  is  gradually 
heated.  The  temperature  at  which  the  substance  becomes  sufficiently  fluid  ta 
run  down  into  the  capillary  part  of  the  tube  is  called  the  point  of  incipient 
fusion.  When  the  substance  has  melted  and  run  down  into  the  shoulder  of 
the  tube,  and  shows  no  trace  of  turbidity,  the  temperature  recorded  is  the 
concluding  point  of  fusion.  Bensemann  records  the  following 
results : — 


Source  of  Cacao-butter. 

Fat. 

Fatty  Acids. 

Initial 
Melting-point. 

Initial 
Melting-point. 

Concluding 
Melting-point. 

Percentage  of 
Insoluble. 

Maracaibo  beans,    . 

25-26°  C. 

48-49°  C. 

51-52°  C. 

94-59 

Caraccas  beans, 

27-28 

48-49 

51-52 

95-31 

Trinidad  beans. 

26-27 

49-50 

52-53 

95-65 

Portoplata  beans,    . 

28-29 

49-50 

52-53 

95-46 

Machala       Guayaquil  \ 
beans,      .      .      .      / 

28-29 

49-50 

52-53 

95-24 

570 


MELTING-POINT   OF   CACAO-BUTTER. 


T.  M.  C 1  a  g  u  e  has  recently  pointed  out  (Pharm.  Jour.,  [3], 
xxiii.  247)  that  the  melting-point  of  commercial  cacao-butter  extends 
over  a  considerably  greater  range  than  the  above,  and  is  materially 
affected  by  the  temperature  to  which  it  has  been  exposed.  Thus, 
the  melting-point  of  ten  trade  samples  ranged  from  73°-91°  F. 
A  sample  expressed  by  heat  direct  from  cocoa-nibs  melted  at  91°, 
while  the  fat  obtained  from  the  same  nibs  by  extraction  with 
ether  melted  at  83°  F.  Similarly,  the  fat  extracted  by  ether  from 
a  "cocoa-essence"  had  a  melting-point  of  96°,  while  the  cacao- 
butter  extracted  by  heat  and  pressure  by  the  same  firm  melted  at 
75°  F.,  thus  showing  that  a  certain  amount  of  fractionation  occurs 
in  the  ordinary  process  of  extraction  by  pressure. 

T.  M.  C 1  a  g  u  e  further  observed  the  following  suggestive 
alterations  of  melting-point  when  cacao-butter  was  heated  to 
various  temperatures.  Nos.  1  and  2  were  ordinary  trade  samples, 
and  hence  had  been  already  heated  in  the  process  of  manufacture. 
No.  3  was  extracted  by  ether  from  unroasted  cocoa-nibs,  and  hence 
excessive  heating  had  been  entirely  avoided  : — 


Melting-point ; 

... 

No.l. 

No.  2. 

No.  3. 

Original, ... 

75 

86 

86 

After  being  heated  to  105°  F., 

75-5 

89 

86 

»        120', 

84 

85 

91 

.,       ir,o\    ....... 

85 

83 

92 

180% 

80 

80 

85 

The  melting-point  of  No.  1  sample  was  raised  to  86°  F.  by 
keeping  it  at  a  temperature  just  under  100°  F.  for  two  hours. 
The  determinations  of  melting-points  were  made  on  metallic 
mercury,  substantially  by  method  c  described  in  Vol.  II. 
page  23.1 

Cacao-butter  contains  the  glycerides  of  stearic,  oleic,  and  a  little 
lauric,  palmitic,  and  arachidic  acids.  C.  T.  Kingzett  obtained 
from  cacao-butter  an  acid  of  the  formula  Cg4Hi28^2J  ^^icli  ^e 
named  theobromic  acid.  P.  Graf  isolated  9*59  per  cent, 
of  glycerol,  and  detected  a  little  cholesterin  and  small  quanti- 
ties of  formic,  acetic,  and  butyric  acids. 

*  T.  M.  Clague  has  also  described  experiments  showing  that  deternnnations 
of  the  melting-point  of  cacao-butter  by  the  capillary  tube  method  are  very 
gravely  afifected  by  the  diameter  of  the  tube  employed. 


EXAMINATION  OF  CACAO-BUTTER.  571 

The  iodine-absorption  of  a  large  number  of  samples  of 
cacao-butter  from  different  sources  has  been  determined  by  F. 
Filsinger  (Ghem.  Zeit,  xiv.  7 1 6),  and  found  to  range  from  3 3 "4 
to  37*5.  The  saponification-equivalent  ranges  a  few  degrees  on 
each  side  of  280,  which  figure  corresponds  to  20'03  per  cent,  of 
potash  (KHO)  required  for  saponification.  Filsinger  found  the 
potash  required  to  range  from  19 "2  to  20*2,  and  Weigmann 
from  19*84  to  20'30.  An  admixture  of  paraffin  wax  would  reduce 
the  percentage  of  alkali  required  for  saponification. 

The  specific  gravity  of  solid  cacao-butter  is  variously  stated.  The 
author  found  the  plummet-gravity  at  98°  C.  to  be  0"8577.  Any 
admixture  of  paraffin  wax  would  reduce  this  figure,  while  cocoa-nut 
oil  would  increase  it. 

Foreign  fats  in  cacao-butter  tend  to  alter  the  foregoing  characters, 
but  observations  of  the  melting-point  and  specific  gravity  do  not 
usually  furnish  satisfactory  means  of  detecting  such  admixtures. 
Tallow  is  said  to  be  capable  of  detection  by  saturating  a  cotton 
thread  with  the  oil,  allowing  it  to  burn  for  a  short  time,  and  then 
blowing  it  out,  when  the  odour  of  tallow  becomes  perceptible. 

A  better  test  for  tallow  and  other  adulterants  of  cacao-butter  is 
to  dissolve  2  grammes  of  the  fat  in  4  grammes  (  =  5'5  c.c.)  of 
ether  at  17°-18°  C.,^  and  then  immerse  the  closely-corked  test- 
tube  in  ice-cold  water.  Granules  will  separate  from,  or  turbidity 
be  produced  with,  pure  cacao-butter,  in  not  less  than  3  and  more 
frequently  in  from  5  to  8  minutes,  sometimes  delayed  to  10  or  15 
minutes ;  while  if  fallow  or  suet  be  present,  a  turbidity  will  appear 
at  once,  or  within  2^  minutes,  according  to  the  proportion  of  the 
adulterant,  of  which  5  per  cent,  may  thus  be  detected.  On  expos- 
ing the  solution  to  a  temperature  of  14°  to  15°,  it  will  gradually 
become  clear  again,  or  more  rapidly  at  20°,  if  the  cacao-butter  was 
pure,  but  not  if  it  was  adulterated.  With  a  sample  containing  5  per 
cent,  of  tallow,  turbidity  occurs  in  8  minutes,  and  the  solution 
does  not  become  clear  below  22°;  while  with  10  per  cent,  of 
tallow,  the  turbidity  occurs  in  7  minutes,  and  the  clearing- point  is 
25°  C.  This  test  is  due  to  Bjorkland  (Zett.  Anal.  Chem.y  iii. 
233),  and  is  adopted  in  the  United  States  Pharmacopoeia.  Its 
value  has  been  confirmed  by  other  observers,  of  whom  Lamhofer 
has  pointed  out  that  petroleum-ether  may  be  employed  with  similar 
results,  except  that  the  cacao-butter  separates  rather  more  slowly 
than  from  ether,  the  deposit  being  always  granular,  while  other  fats 
render  the  entire  liquid  cloudy.  The  solution  of  cacao-butter  in 
two  parts  of  ether  will  remain  clear  for  an  entire  day  if  maintained 

^  A  failure  to  obtain  a  clear  solution  points  to  the  presence  of  paraflSn  wax. 


672 


EXAMINATION   OF  CACAO-BUTTER. 


at  a  temperature  of  12°  to  15°  C.  This  modification  of  the  test  is 
prescribed  by  the  German  Pharmacopoeia,  and  is  due  to  R  a  m- 
sperger,  who  states  that  aniline  may  be  substituted  for  the 
ether.  Fil singer  (Zeit.  Anal.  Chem.,  xix.  247)  has  described 
the  following  modification  of  the  ether-test : — Two  grammes  of  the 
fat  should  be  melted  in  a  graduated  tube  with  6  c.c.  of  a  mixture 
of  4  volumes  of  ether  (sp.  gr.  0*725)  and  2  volumes  of  alcohol 
(sp.  gr.  0'810),  shaken,  and  set  aside.  Pure  cacao-butter  gives  a 
solution  which  remains  clear. 

According  to  E.  Dietrich,  a  very  reliable  test  for  the  purity 
of  cacao-butter  consists  in  warming  the  sample  with  an  equal 
weight  of  paraffin  oil.  A  drop  of  the  mixture  is  placed  on  a  slip 
of  glass,  a  thin  cover  applied,  and  the  slide  exposed  for  twelve 
hours  to  a  temperature  not  exceeding  5°  C.  When  then  examined 
with  polarised  light,  under  a  magnifying  point  of  20  diameters,  the 
crystals  of  cacao-butter  present  the  appearance  of  palm-leaves, 
showing  a  fine  play  of  colours  with  selenite.  An  addition  of 
10  per  cent,  of  beef-tallow  causes  the  fat  to  crystallise  in  tufts  of 
needles,  or  circular  groups  of  crystals,  which  exhibit  a  black  cross ; 
while  if  mutton-tallow  be  the  adulterant,  it  is  stated  that  no  cross 
can  be  seen. 


7. 

8. 

9. 

10. 

11. 
12. 
13. 


References  to  Photographs  of  Leaves. 

{See  page  522.) 
Plate  I.  Plate  II. 


Camellia  Thea.     Tea. 

Marattia  Elegans. 

EpilohiumAngiistifolium.  French 
Willow  or  Willow  Herb. 

Salix  Alba.     Willow. 

Tlex  Paraguayeiisis.  Paraguay 
Tea  or  Brazilian  Holly. 

Popultcs  Nigra.     Poplar. 

Sam^itcus  Nigra.     Elder. 

Ulmtis  Campestris,     Elm. 

Betula  Alba.     Biich. 

Prurms  Spinosa.  Sloe  or  Black- 
thorn. 

Prunus  Cerastes.     Cherry. 

Rubus  IdcBus.     Raspberry. 

Camellia  Sasanqua. 


14.  Camellia  Thea.     Tea. 

15.  Ribes  Grossularia.      Gooseberr}'. 

16.  Rosa  Canina.     Dog  Rose. 

17.  Coffea  Arabica.     Coffee. 

18.  Cratcegus     Oxyacantha.        HaAv 

thorn. 

19.  Fragaria  Vesca.     Strawberry. 

20.  Pyrus  Malus.     Apple. 

21.  Quercus  Robur.     Oak. 

22.  Ribes  Nigrum.     Black  Currant 

23.  Fraximis  Excelsior.     Ash. 

24.  Fagus  Sylvatica.     Beech. 

25.  Rubus      Fructicosus.         Black- 

berry. 

26.  Prunus  Communis.     Plum. 


PUte  I, 


A.S.Huth.Lith'  U 


Plate  II 


25. 


A.S.Huth.Lith'".  London 


INDEX. 


AOETAMIDE,  2 

Acetanilide,  63,  67,  68 

detection  of,  69,  83,  84 

Aceto-amidophenol,  68 
Aceto-anisidine,  68,  85 
Acetophenone,  68 
Acet-phenethidine,  68,  81 
Acet-phenylhydrazine,  28,  68 
Acid,  aconitic,  207 

amalic,  480 

amidobenzene-sulphonic,  49 

amidonaplithol-sulphonic,  94 

aniline-sulplioiiic,  49 

atropic,  245 

berberonic,  112,  4G3 

boheic,  501 

caffeic,  529 

caflfeidine-carboxylic,  479 

caflfelannic,  529 

chelidonic,  166 

chlorogenic,  529 

chrysatropic,  262 

cinchomeronic,  112,  165 

cinchofulvic,  445 

cinchotannic,  444 

cocaic,  286 

cocatannic,  291 

columbic,  472 

comenic,  337 

cotarnic,  299 

diniethyl-parabanic,  4S1 

dipicolinic,  112 

hemipinic,  298,  463 

hydrochloric,  as  a  reagent,  145 

hydroquinine-sulphonic,  425 

hydrastinic,  470 

igasuric,  384 


Acid,  isatropic,  246,  286 

isococaic,  287 

isonicotinic,  111 

kinic,  445 

leucotropic,  263 

lutidinic,  112 

lycoctonic,  225 

meconic,  336 

„        detection  of,  338,  358 

metatungstic,  as  a  reagent,  137 

methylparabanic,  494 

nicotinic,  111 

nitric,  as  a  reagent,  146 

opianic,  203,  298 

phosphoantimonic,  as  a  reagent 

137 

phosphomolybdic,  136 

phosphotungstic,  136 


picolinic.  111 

picric,  as  a  reagent,  134 

pyridine-carboxylio,  110,  112 

pyromeconic,  337 

quinic,  445 

quinolinic,  112 

quinovic,  444 

silicotungstic,  as  a  reagent,  137 

strychnic,  384 

strychnine-monosulphonic,  363 

sulphanilic,  49 

sulphomolybdic,  as  a  reagent,  147 

sulphoselenic,  as  a  reagent,  145 

sulphovanadic,  as  a  reagent,  148 

sulphuric,  as  a  reagent,  145 

tannic,  as  a  reagent,  135 

tannic,  in  tea,  491,  515 

tropic,  245 

trimethyl-thiocarbamic,  IG 


574 


INDEX. 


Acid,  uric,  colour-reaction  of,  473 

Acolyctine,  224 

Aconine,  202,  204,  214,  232,  235 

Aconite,  assay  of,  228 

official  preparations  of,  199 

poisoning  by,  236 

toxicological  detection  of,  24  J 

various  species  of,  199,  201 

Aconitine,  207 

amorphous,  201,  215,  218 

anliydro-,  205,  213 

characters  of,  202,  209 

composition  of,  205 

constitution  of,  203,  205 

detection  of,  211,  240 

determination  of,  231 ,  233 

poisoning  by,  209,  236 

saponification  of,   133,  203,  213, 

233 

titration  of,  231 

Acridine,  123 

Alkaloids,  aconite,  198,  201,  202 

behaviour  of,  with  immiscible  sol- 
vents, 154,  158,  159 

of  belladonna,  263 

of  berberis,  461,  465 

of  celandine,  295 

of  chelidonium,  295 

of  cinchona,  391 

of  coca,  270 

colour-reactions  of,  144 

of  dita  bark,  437 

effect  of,  on  the  pupil,  150 

of  eschscholtzia,  296 

extraction  of,  by  immiscible  sol- 
vents, 154,  158,  159 

extraction  of,  from  plant-products, 

151,  160 

general  precipitants  of,  134,  153 

of  hemlock,  171 

of  henbane,  250,  267 

of  hydrastis,  461,  467 

isolation  of,  151 

of  lupine,  178 

mydriatic,  244 

of  nux  vomica,  384 

of  opium,  293 


Alkaloids,  of  Remijia  barks,  384 
oxidation  colour-reactions  for,  149, 

314,  368,  469,  480 

physiological  tests  for,  149 

purification  of,  162 

1  eactions  of,    with    Czumpelitz's 

reagent,  144 

Dragendorff  s  reagent,  138 

Erdmann's  reagent,  148 

ferric  chloride,  148,  304,  313 

Frohde's  reagent,  147 

Hager's  reagent,  134 

hydrochloric  acid,  145 


Kundrat's  reagent,  148 

Mayer's  reagent,  138,  153 

Marme's  reagent,  138 

nitric  acid,  146 

Scheibler's  reagent,  136 

Sonnenschein's  reagent,  136 

— ^ sulphuric  acid,  145 

"Wagner's  reagent,  137 

Wormley's  reagent,  137 

zinc  chloride,  144 

strychnos,  362 

Alpha-naphthylamine,  90,  91 
Alloxantin,  480 
Alstonine,  437 
Amido-benzene,  43 

sulphonic  acids,  49 

naphthols,  94 

-naphthol -sulphonic  acids,  95 

paraphenacetin,  85 

-pentamethylbenzene,  60 

phenols,  80 

thiophene,  63 

Amines,  classification  of,  1 

distinction  of,  7 

ferrocyanides  of,  8 

reaction  of,  with  nitrous  acid,  7 

with  aldehydes, 

separation  of,  4 

Amiuol,  15 
Ammonium  bases,  18 
Analgesin,  32 
Anhydro-aconitine,  205,  213 

-bases  of  aconite,  205 

-ecgonine,  251 


INDEX. 


675 


Anliydro-tropines,  251 
Antifebrin,  68 
Antithenniu,  31,  68 
Antipydne,  32 

chloral-,  38 

nitroso-,  34 

Antiseptin,  68,  71 
Apo-aconitine,  213 
Apo-atropine,  251 
Apo-bases,  see  Anbydro-bases 
Apocodeine,  324 
Apornorpbine,  319 
Arginine,  167,  178 
Aricine,  393,  436 
Atisine,  226 
Atropamine,  244,  251 
Atropine,  and  its  allies,  243 

anhydro-,  251 

constitution  of,  165,  244 

products  of  saponification  of,  244 

reactions  of,  254 

toxicological  detection  of,  261 

Azobenzene,  63 
Azo  dyes,  42 
Azoimide,  24 

Bases  from  tea,  39 
Belladonna,  alkaloids  of,  263 

assay  of,  264 

composition  of,  262 

extract  of,  269 

Belladonnine,  244,  252 
Benzanilide,  72 
Benzidine,  88 
Benzoyl-aconine,  207 

-anbydro-aconitine,  206 

-ecgonine,  270,  282 

-japaconitine,  221 

methylecgonine,  see  Cocaine 

pseudotropine,  244,  287 

-tropine,  253 

Beuzylamine,  51 
Berbamine,  461,  466 
Berberine,  461 

salts  of,  464 

Berberis  alkaloids,  461 
Beta-naphthylamine,  90,  92 


Bromacetanilide,  68,  71 
Bruciue,  381 

constitution  of,  168,  381 

dinitro-,  382 

reactions  of,  382 

separation    of,    from  strychnine, 

366 
Butylamine,  14 

Caffeidine,  479 

carboxylic  acid,  479 

Caffeine,  474 

assay  of  tea  for,  490 

constitution  of,  167,  473 

determination  of,  484 

natural  occurrence  of,  474 

presence  of,  in  cocoa,  495 

proportion  of,  in  tea,  492 

in  coffee,  528,  552 


reactions  of,  480 

salts  of,  482 

solubilities  of,  477 

Calumba  root,  471 

Camphor,  compound  tincture  of,  853 

Canadine,  470 

Carbazol,  113 

Cevadine,  constitution  of,  133,  166 

Cevine,  133,  166 

Chairamidine,  393,  436 

Chairamine,  393,  436 

Chelidonine,  295 

Chelerythrine,  295 

Chicory,  composition  of,  538,  544 

detection  of,  in  coffee,  540 

determination  of,  542,  545,  550 

Chinoliue,  see  Quinoline 
Chinovin,  443 
Chloral-antipyrine,  38 
Cholestrophane,  481 
Chocolate,  561 
Choline,  18,  133,  167 
Cinchamidine,  433 
Cincholeupone,  168 
Cinchona  alkaloids,  391 

amorphous,  433 

general  properties  of,  394 

proportion  of,  in  bark,  445 


576 


INDEX. 


Cinchona  alkaloids,  separation  of,  453 

list  of,  392 

barks,  440 

assay  of,  449 

composition  of,  442 

proportion    of   alkaloids   in, 

445 
Cinchonaniine,  392,  436,  438 
Cinchona-red,  445 
Cinchonicine,  435 
Cinchonidine,  392,  397,  428 

constitution  of,  168 

determination  of,  410,  413,   430, 

449,  459,  460 

homo-,  430 

hydro-,  432 

Cinchonine,  392,  397,  431 

constitution  of,  168 

decomposition-products  of,  168 

determination  of,  413,  459,  460 

hydro-,  392,  432 

Cinch otannin,  444 
Cinchotenine.  168 
Cinchotine,  392,  432 
Cinnamyl-cocaine,  271,  285 

ecgonine,  270,  272 

Coca,  alkaloids  of,  270 

amorphous  bases  of,  287 

leaves,  290 

extraction  of  alkaloids  from, 

292 
Cocaine,  273 

amorphous,  287 

cinnamyl-,  285 

commercial,  278 

constitution  of,  166,  271 

decomposition-products  of,  282 

dextro-,  284 

homo-,  285 

hydrochloride,  277 

saponitication  of,  272,  282 

Cocamine,  271,  272,  286 

Cocethyliue,  285 

Cocoa,  adulterations  of,  561 

analysis  of,  564 

commercial,  561 

butter,  558,  568 


Cocoa,  composition  of,  556 

essence  of,  661 

husks,  556,  557,  561 

nitrogenous  constituents  of,  559 

Codamine,  294,  301,  304.  320 
Codeine,  294,  321 
Cotfee,  527 

adulterations  of  ground,  538 

beans,  533 

caramel  in,  539 

composition  of,  528 

detection  of  chicory  in,  540 

detection  of  starch  in,  541 

factitious,  535 

imitation,  535 

-parchment,  528 

physiological  action  of,  632 

roasting  of,  530 

Colchicine,  166 
Collidines,  97,  109 
Columbin,  472 
Conchairamine,  398,  436 
Concusconine,  393 
Conhydrine,  171,  173 
Coniceines,  174 
Conine,  171 

assay  of  hemlock  for,  176 

determination  of,  176 

poisoning  by,  175 

Conium,  176 

alkaloids  of,  171 

tincture  of,  177 

Conquinamine,  372,  427 
Conquinine,  see  Quinidine 
Cotarnine,  299 

Cryptopine,  294,  301,  304,  324 
Cumidines,  59,  63 
Cupreine,  392,  397,  438 

constitution  of,  169,  398,  439 

separation  of,  413,  438 

Curare,  387 
Curarine,  371,  389 
Curine,  390 
Cuscamidine,  393 
Cuscamine,  393 
Cuscouidiue,  393 
Cusconine,  393 


INDEX. 


577 


Deutekopine,  295,  324 
Diamide,  22 
Diamidogen,  22 
Diaraido-benzenes,  86 
Diamido-phenols,  83,  85 
Diantipyrine,  31 

Diazo-compounds,  formation  of,  7 
Dicinchonicine,  393,  435 
Diethylaniline,  73,  79 
Diethylene-diamine,  2,  106 
Dietliyl-hydrazine,  26,  27 

oxamide,  5 

Dimethylamine,  12 

reactions  of,  10 

Dimethylaniline,  73,  74 
commercial,  76 


Exalgin,  68,  71 
Extract  of  aconite,  229 

belladonna,  266,  269 

cinchona,  445 

cocoa,  561 

coffee,  553 

hemlock,  77 

henbane,  269 

nux  vomica,  386 

opium,  350 

tea,  505 

Flavaniline,  69 
Forrayl-paraphenethidine,  85,  373 
Furfuran,  113 


Dimethylnitrosamine,  7 

Gelsemine,    colour-reactions  of,  145, 

Dinaphthylene-diamines,  93 

146,  149,  437,  469 

Dinitrobenzenes,  63 

Glaucine,  296 

DipLenylainine,  79 

Glaucopicrine,  296 

Diphenylaniline,  79 

Glucosides,  behaviour  with  immiscible 

Diphenylene-diainines,  86 

solvents,  158,  159 

Diquinicine,  393,  435 

colour-reactions  of,  146,  147,  148 

Dita  bark,  436 

Gnoscopine,  294,  301,  324 

Ditaine,  436 

Ditamine,  436 

Hemlock,  assay  of,  176 

Ditoluylene-diamine,  87 

lesser-,  175 

Dinretin,  497 

poisoning  by,  175 

tincture  of,  177 

Easton's  syrup,  376 

water-,  175 

Echitamine,  436 

Henbane,  alkaloids  of,  250,  267 

Echitenine,  436 

assay  of,  267 

Ecgonine,  283 

extract  of,  269 

anhydro-,  284 

Herepathite,  138,  402,  454 

benzoyl-,  282 

Homatropine,  253,  254 

constitution  of,  166,  270,  284 

Horaoquinine,  439 

Ethyl  di ethyl oxamate,  5 

Hydracetin,  28,  68 

oxalate,  5 

Hydrastine,  461,  467 

Ethylamine,  14 

colour-reactions  of,  469 

reactions  of,  10,  17 

Hydrastinine,  470 

Ethylamines,  17 

Hydrazine,  22 

Ethylaniline,  73 

ethyl-,  26 

Ethyl-hydrazine,  26 

hydrate,  22 

morphium  compounds,  18 

phenyl-,  27 

strychnium  compounds,  19 

salts,  23 

thalline,  121 

Hydrazines,  22 

Euphorin,  68,  72 

substituted,  25 

VOL.  III.  part  II. 

2  0 

578 


INDEX. 


Hydrazobenzene,  89 
Hydrazones,  30 
Hydrazonium  compounds,  25 
Hydroacridine,  126 
Hydrocinchonidine,  392,  410,  430 
Hydrocinchonine,  392,  432 
Hydrocotarnine,    294,   301,  304,    309, 

325 
Hydrohydrastinine,  470 
Hydroquinicine,  425 
Hydroquinine,  424,  410,  415 
Hyoscine,  244,  250 

reactions  of,  254 

saponification  of,  244 

Hyoscyamine,  244,  249 

reactions  of,  254 

saponification  of,  244 

Hyoscyamus,  see  Henbane 
Hypnone,  68 
Hygrine,  289 

Imidazoic  acid,  24 — 

Immiscible  solvents,  behaviour  of  alka- 
loids with,  159 

behaviour  of  organic  sub- 
stances with,  158 

extraction  by,  154 

Inflatin,  196 

lodol,  114 

Iridoline,  115 

Isoduridine,  60 

Isotropine,  270 

Japaconitine,  202,  204,  220 

benzoyl-,  221 

saponification  of,  204,  221,  233 

Javanine,  392 

Kairine,  120 
Kairoline,  119 
Kakotelin,  383 
Kola,  554 
Kynurine,  168 

Lanthopine,  294,  301,  304,  308,  325 
Laudanine,  294,  301,  304,  308,  325 
Laudanosine,  294,  301,  304,  309,  325 
Laudanum,  350 
Lobelia,  alkaloids  of,  195 


Lobeline,  195 
Logan  etin,  385 
Loganin,  385 
Lupanine,  179 
Lupine  alkaloids,  178 
Lupinidine,  179 
Lupinine,  ]67,  178 
Lutidine,  97,  108 
Lyaconine,  224 
Lyaconitine,  202,  222 
Lycoctonine,  224 

Mate,  526 
Meconates,  339 
Meconarceine,  327 
Meconic  acid,  336 

detection  of,  338,  358 

Meconin,  298,  335 
Meconidine,  294,  301,  308,  326 
Meconoisin,  336 
Metaphenylenediamine,  86 
Metatoluidine,  52 
Methacetin,  68,  85 
Methocodeine,  167,  296,  324 
Methyl  chloride,  manufacture  of,  16 
Methyl-ace tanilide,  68,  71 
Methyl-alloxantin,  494 
Methylamine,  9 

reactions  of,  10 

Methylaniline,  63,  71 

nitrosamine,  74 

paranitroso-,  74 

Methyldiphenylamine,  79 
Methylphenacetin,  84 
Metaxylidines,  57,  59 
Monamines,  3 

characters  of,  8 

distinction  of,  7 

separation  of,  5 

Morphine,  294,  309,  326 

assay  of  opium  for,  342 

colour-reactious  of,  302,  305,  813 

constitution  of,  167,  296,  311 

detection  of,  313 

poisoning  by,  356 

proportion  of,  in  opium,  333 

salts  of,  311 


INDEX. 


579 


Morphine,  separation  of,  305 

solubilities  of,  301,  310 

toxicology  of,  355 

Morphiometry,  342 
JVIurexide,  480 
Murexoin,  480 
Myoctonine,  202,  222,  225 

Naphthylamines,  90 
Naphthylamine-sulphonic  acids,  9 
Naphthylene-diamines,  93 
Narceine,  294,  301,  302,  303,  326 

constitution  of,  299 

determination  of,  305,  306 

Narcotine,  294,  298,  301,  302,  327 

constitution  of,  167,  298 

determination  of,  305 

Neurine,  19 
Nicotine,  179 

constitution  of,  164 

determination  of,  161,  170,  182 

poisoning  by,  183 

Nitranilines,  50,  63 
Nitrobenzene,  recognition  of,  67 
Nitrosamines,  formation  of,  7,  74 
Nitroso-antipyrine,  34 

-dimethylaniline,  75 

Nitrous  acid,  action  on  monamines,  7 
Nornarcotine,  298 
Nux  vomica,  384 

assay  of,  385 

preparations  of,  38^ 

Orthotoluidine,  90 

Opianine,  329 

Opiates,  composition  of  various,  357 

Opionin,  336 

Opium,  332 

action  of  solvents  on,  339 

adulterations  of,  340 

alkaloids  of,  293,  333 

assay  of,  for  morphine,  342 

composition  of,  333 

detection  of,  358 

extract  of,  350 

poisoning  by,  355 

— -  proportion  of  alkaloids  in,  333, 335 


Opium,  tincture  of,  350 
Opium  alkaloids,  293,  333 

colour-reactions  of,  302 

constitution  of,  167,  296 

proportions  of,  in  opium,  333 

separation  of,  305 

tabular  list  of,  294 

poisonous  characters  of,  294 

Orexin,  122 

Orthine,  29 

Orthotoluidine,  52 

Orthoxylidines,  57,  59 

Osazones,  30 

Oxidation   colour-reactions,   149,  302, 

314,  368,  469,  480 
Oxyacanthine,  465 
Oxydimorphine,  see  Pseudomorphine 
Oxyhydrastinine,  470 
Oxynarcotine,  294,  329 

Papaverine,  294,  301,  302,  304,  306 
329 

constitution  of,  168,  299 

Papaverosine,  294,  329 

Parabromacetanilide,  68,  71 

Paraguay  tea,  526 

Paraniline,  63 

Paraxylidine,  57 

Paregoric  elixir,  353 

Parvoline,  97 

Paytamine,  392 

Paytine,  392 

Piazine,  constitution  of,  96 

Picoline,  97,  107 

Picraconitine,  202,  204,  221 

Picramide,  51 

Pilocarpine,  synthesis  of,  166 

Piperazidine  or  Piperazine,  106 

Piperidine,  106,  164 

Piperine,  133,  164 

Piturine,  194 

Phenacetin,  68,  81 

PhenacoU,  68  , 

Phenethidines,  81 

Phenanthridine,  126 

Phenazone,  32 

Phenylacetamide,  68 


580 


INDEX. 


Phenylamine,  see  Aniline 
Phenyl-aniline,  73,  79 
Pheuyl-carbamine,  46 
Phenyl-dimethylpyrazolone,  32 
Phenylene-diamines,  63,  86 
Phenyl-hydrazides,  28 
Phenyl-hydrazine,  27 
Phenyl-methylpyrazolone,  31 
Phenyl-pyrazolone,  31 
Phenyl-urethane,  68,  72 
Poisoning  by  acetanilide,  71 

aconitine,  209,  236 

aniline,  44,  46 

antipyrine,  37 

apomorphine,  320 

atropine,  248,  261 

berberine,  462 

brucine,  382 

cocaine,  274 

cocamine,  286 

codeine,  322    _ 

coniceines,  174 

Conine,  175 

curare,  388 

ethylstrychniura,  19 

hemlock,  175 

hydracetin,  28 

hydrazine,  23 

hyoscyamus,  261,  250 

laudanine,  325 

lobelia,  195 

lupinine,  178 

metaphenylenediamine,  87 

methacetin,  85 

nicotine,  183 

0]>iates,  357 

ojiium,  355 

opium  bases,  294 

paraphenylenediamiue,  57 

phenacetin,  83 

protopine,  330 

pyridine,  98,  103 

sparteine,  197 

spigeline,  198 

strychnine,  372 

thebaine,  331 

tobacco,  183 


Poisoning  by  toluylene-diaraines,  88 

vermin-killers,  380 

Porphyrine,  437 
Porphyroxine,  296,  330,  335 
Precipitants,  general,  for  alkaloids,  134, 

158 
Propylamine,  12 
Protopine,  296,  301,  304,  330 
Pseudaconine,  202,  204,  219 
Pseudaconitine,  202,  204,  216 

anhydro-,  205 

saponification  of,  204,  218,  234 

Pseudocodeine,  323 
Pseudomorphine,  294,  301,  302,  330 

constitution  of,  298 

Pseudotropine,  244,  247 

benzoyl,  244,  287 

Puccine,  296 
Pyrazine,  80,  96 
Pyrazole,  30,  96 
Pyrazolines,  30 
Pyrazolones,  30 
Pyridine,  96,  99 

assay  of  commercial,  104 

bases,  96 

-carboxylic  acids,  110,  165 

detection  of,  104 

homologues  of,  107 

salts  of,  101. 

Pyridone,  96 
Pyrodine,  28 
Pyrone,  96 
Pyrrol,  96,  113 

methyl-,  114 

tetraiodo-,  114 

Pyrroline,  96 

QUINALDINE,  115 
Quinamicine,  427 
Quinamidine,  392,  427 
Quinamine,  392,  397 

constitution  of,  169 

Qninazoline,  115 

Quinetum,  448 

Qninicine,  433 

Quinidine,  393,  425 

determination  of,  426,  459 


INDEX. 


581 


Quinidine,  reactions  of,  397,  426 
Quinine,  393 

constitution  of,  168 

decomposition-products  of,  168 

determination  of,  in  bark,  449, 455 

distinction  of,  from  allied  bases, 

405 

formation  from  cupreine,  169,  398 

hydro-,  424 

iodosulphate  of,  403,  454 

iron  citrate,  421 

precipitation    of,  as   herepathite, 

403,  454 

reactions  of,  400 

salts  of,  406 

sulphate,  406 

examination  of,  408 

impurities  in,  408 

synthetical  isomers  of,  169 

tannate  of,  420 

tincture  of,  423 

wine  of,  424 

Quinoidine,  433 

iodosulphate  of,  454 

Quiuoline,  114,  116 

tetrahydro-,  119 

Resopyrin,  37 
Rhceadine,  294,  301,  331 
Rubidine,  97 

Sanguinarine,  295 

Salicin,  colour-reactions  of,  146,  147, 

370,  409 
Saliityrin,  37 

Santonin,  colour-reactions  of,  148,  370 
Scopolamine,  244,  251 
Scopoletin,  262 
Sina]»ine,  133,  167 
Snutf,  193 
Solanine,  occurrence  of,  262 

reactions  of,  146 

Solvents,  action  of,  on  opium,  339 

on  jilant-con.stituents,  151 

immiscible,  use  of,  154 

Sparteine,  197 
Spigfline,  198 


Stramonium,  268 
Strychnine,  361 

assay  of  nux  vomica  for,  385 

constitution  of,  168 

detection  of,  374 

monobrom-,  363 

monosulphonic  acid,  363 

oxidation-test  for,  368,  469 

poisoning  by,  372 

preparations  of,  376 

ptomaine  simulating,  371,  375 

reactions  of,  364 

separation  of,  from  brucine,  366 

toxicology  of,  372 

vermin -killers  containing,  376 

Strychnos  nux  vomica,  384 
Stylophorine,  296 
Sulphanilic  acid,  49 

Tab  bases,  39 
Tea,  499 

adulterations  of,  509 

alkaloid  in,  419,  492,  504 

Arabian,  527 

ash  of,  511 

Assam,  506 

Bush,  503 

Cape,  503 

caper,  520 

catechu  in,  519 

Ceylon,  506,  512 

China,  512 

chlorophyll  in,  505 

composition  of,  501 

essential  oil  of,  601 

exhausted  leaves  in,  51.? 

extract  of,  505 

facing  of,  522 

foreign  leaves  in,  522 

Indian,  503,  512 

infusion  of,  505 

Japanese,  502,  506 

Java,  512 

leaves,  recognition  of,  r>23 

lie-,  520 

mineral  adulterants  of,  51 0 

moisture  in,  504 


582 


INDEX. 


Tea,  Natal,  503,  612 

Paraguay,  526 

preparation  of,  499 

sloe  leaves  in,  502,  605 

tannin  in,  515 

tasting,  507 

Trebizonde,  527 

Tannin,  in  colfee,  529 

in  tea,  491,  515 

reactions  of  alkaloids  with,  135 

Tetra-alkylated  ammoniums,  18 
Tetrahydro-beta-naphthylamine,  92 
Tetraiodo-pyrrol,  114 
Tetrethyl-ammonium  compounds,  19 
Thalleioquin  reaction,  396,  397,  401 
Thalline,  120 

ethyl-,  121 

Thebaine,  294,  331 

colour-reactions  of,  302,  331 

constitution  of,  167,  296 

determination  of,  306,  307,  332 

solubilities  of,  301 

Theobromine,  492 

characters  of,  493 

constitution  of,  492 

determination  of,  494 

in  tea,  489 

proportion  of,  in  cocoa,  496,  568, 

560 
Theophylline,  498 
Thermifugin,  122 
Thermine,  92 
Tincture  of  camphor,  compound,  353 

aconite,  229 

belladonna,  266 

conium,  177 

hemlock,  177 

henbane,  268 

nux  vomica,  357 

opium,  350 

quinine,  423 

Tobacco,  184 

ash  of,  186,  188,  189,  190 

combustibility  of,  190 

composition  of,  184 

extract,  193 

nitrogen  in,  187,  189,  190 


Tobacco,  poisoning  by,  183 

smoke,  composition  of,  192 

Tolidine,  90 

Toluidine,  commercial,  54 

density  of,  56 

oxalates,  55 

phosphates,  54 

Toluidines,  41,  51 
Toluylene-diamines,  87 
Triamidophenol,  85 
Trimethylamine,  12 

hydrochloride,  16 

reactions  of,  10 

Triphenylamine,  80 
Triphenylrosaniline,  64,  66 
Tritopine,  294,  301,  332 
Tropeines,  243 

artificial,  253 

saponification  of,  244 

Tropine,  constitution  of,  165,  246 

benzoyl-,  253 

properties  of,  246 

pseudo-,  247 

salicyl-,  253 

Truxilline,  271,  281 

Uric  Acid,  colour-reaction  of,  480 

Veratrine,  constitution  of,  133,  IW 
Vermin -killers,  378 
Vinasses,  13 
Viridine,  97 

Wine  of  quinine,  424 

Xanthine,  constitution  of,  473 

colour-reaction  of,  481 

dimethyl-,  473,  492 

derivatives  of,  473 

isolation  of,  from  tea,  473 

trimethyl-,  473,  474 

Xanthopuccine,  471 
Xenylamine,  63 
Xylidines,  57,  63 

Yerba,  526 
Yqpan,  527 


ADDENDA.* 


Page  4.     Separation  of  Methylamines.     M.  Del6pine,  Compt.  r&nd. ,  cxxii. 

1064,  1272 ;  abst.  Jour.  Chem.  Soc,  Ixx.  i.  519,  588  ;  Ixxii.  i.  586. 
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•Compiled,  at  the  request  of  the  Author,  by  A.  R.  Tankard  and 
S.  E.  Melling. 


584  ADDENDA. 

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Studer,  J.S.C.L,  1899,  xviii.  110. 
Page  63.     Assay  of  Alkyl-aniliues,     W.    Vaubel,  Chem.  Zeit.,  xvii.   465; 

abst.  J.C.S.,  Ixiv.  605. 
Page  64.     Analysis  of  Aniline  Oils.     H.    Reinhardt,  Chem.   Zeit.,  xvii. 

413  ;  abst.  Analyst,  1893,  xviii.  150. 
Page  68.     Micro-chemical  tests  for  Acetanilide,  Phenacetin,  etc.     S  c  h  o  e  p  p, 

Pharm.  Zeit.,  xlii.  106  ;  abst.  J.S.C.L,  1897,  xvi.  361. 
Page  68.     Detection  of  Acetanilide  in  synthetical  remedies.     F.  X.  Moerk, 

Amer.  Jour.  Pharm.,  1896,  p.  394. 
Page  68.     Properties  of  Phenocoll  hydrochloride.     S c h  e  r  i  n  g,  Apoth.  Zeit., 

vi.  249  ;  abst.  J.S.C.L,  x.  790. 
Page  68.     Characters   of  Acetanilide.     F.  B.  Power,  Pharm.  Jour.,  1900, 

Ixv.  145. 
Page  69.     Examination  of  Acetanilide.     C.  Piatt,  Jour.  Anal,  and  App. 

Chem.,  vii.  77  ;  abst.  Analyst,  1896,  xxi.  138. 
Page  69.     Detection  of  Acetar.ilide.     F.  X.  Moerk,  Amer.  Jour.  Pharm., 

1896,  p.  389  ;  abst.  Analyst,  xxi.  291.     See  also  Analyst,  1896,  xxi.  69. 
Page  75.     Action  of  acetic  anhydride  on  Dimethylaniline.     Reverdin  and 

de  hi  Harpe,  Bull.  Soc.  Chim.,  vii.  211  ;  abst.  J.C.S.,  Ixiv.  i.  23, 
Page  81.     Dulcine.     See  Vol.  III.  Pt.  iii.  page  279  and  Addenda. 
Page  82.     Preparation  and  characters  of  Phenacetin,  Pharm.  Jour. ,  1 899,  i.  512. 
Page  82.     A    reaction    for    Phenacetin.     Autenreith  and  Hinsberg, 

Arch,  de  Pharm.,  cexxix.  456  ;  abst.  Analyst,  1892,  xvii.  56. 
Page  82.     Properties  of  Phenacetin.     G.  Cohn,  Annalen,  1899,  cccix.  233; 

abst.  J.G.S.,  Ixxviii.  i.  29. 
Page  83.     Colour-reactions  for  Phenacetin,    Methacetin,   etc.,   in   mixtures. 

T.  G.  Selmi,  Chem.  Zeit.,  xvi.  368  ;  abst.  J.S.C.L,  1893,  xii.  466. 
Page  83.     Gu  asti  states  that  Schwartz's  test  for  the  detection  of  Acet- 
anilide is  unreliable.     See  J.C.S.,  Ixvi.  432. 
Page  85.      Preparation  of  Phenacyl-Phenacetin.     C.  Goldschmidt,  Chem. 

Zeit,  1901,  XXV.  628;  abst.  J.S.C.L,  xx.  929. 
Page  88.     Pliysiological  action  of  Toluylene-diamine.     W.  Hunter,  Jour. 

Pathol,  and  Bacterial.,  1895,  p.  259  ;  abst.  J.C.S.,  Ixviii.  ii.  456. 
Page  89.     Determination  of  Benzidine   and  Tolidine.     W.    Vaubel,   Zeit. 

anal.  Chem.,  xxxv.  163  ;  abst.  J.C.S.,  Ixx.  ii.  507. 
Page  89.     Colour-reaction    for    the    detection  of    Benzidine    and   Tolidine. 

J.  Wolff,   Chem.  Centr.,  1899,  ii.  569  ;  abst.  J.C.S.,  Ixxviii.  ii.  119. 
Page  91.     o-Naphthylamine  has  not  much  smell,  the  disgusting  odour  com- 
monly ascribed  to  it  being  mainly  due  to  impurities.     A  pure  article 

having  a  melting  point  of  47°  C.  is  now  made  on  a  commercial  scale. 
Page  92.     Assay  of  Naphthylamine-sul phonic  acids.     W.  Vaubel,  Chem. 

Zeit.,  xvii.  1265  ;  abst.  J.C.S.,  Ixvi.  ii.  74. 
Page  92.     Preparation  of  /3-Naphthylamine-sulphonic  acid.     A.  G.  Green, 

J.S.C.L,  1889,  viii.  878;  1890,  ix.  934. 


586  ADDENDA, 

Page  101.  Action  of  chloranil  on  Pyridine.  H.  Imbert,  Bull.  Soc.  Chim., 
1898,  xix.  1008;  abst.  J.C.S.,  1899,  Ixxvi.  i.  633. 

Page  102.  The  Chlorine  derivatives  of  Pyridine.  Sell  and  D  o  o  t  s  o  n,  Jour. 
Chem.  Soc,  1898,  Ixxiii.  432,  442  ;  1899,  Ixxv.  979;  1900,  Ixxvii.  i.  233. 

Page  103.  Action  of  cadmium  salts  on  Pyridine  and  Piperidine.  R.  Varet, 
Compt.  rend.,  cxv.  464;  abst.  J.C.S.,  Ixiv.  i.  43. 

Page  103.  Action  of  tannin  on  Pyridine  and  Piperidine.  0.  deConinck, 
Compt.  rend.,  cxxiv.  506  ;  abst.  J.S.G.L,  1897,  xvi.  470. 

Page  1C6.     Piperidine  and  Piperazine.     See  also  Vol.  III.  Pt.  iii.  pp.  38,  194. 

Page  107.  Properties  of  Piperidine  Urate.  Tunnicliffe  and  Rosen- 
heim, Brit.  Med.  Jour.,  5th  February,  1898. 

Page  107.  Potassio-iodide  of  bismuth  precipitates  Piperidine  from  its  solu- 
tions on  concentration  and  cooling,  in  the  form  of  thin,  transparent, 
yellow  hexagonal  plates,  of  characteristic  microscopic  appearance. 

Page  114.  Source  and  properties  of  "lodol."  k.  H viW&t,  Monit.  Scient.f 
1892,  p.  338  ;  abst.  J.S.G.L,  xi.  1030. 

Page  114.  Action  of  nitric  acid  on  *'Iodol."  H.  Cousin,  Jour.  Pharm, 
Chim.,  xiii.  269  ;  abst.  J.S.C.I.,  1901,  xx.  497. 

Page  128.  Localisation  of  Alkaloids  in  Plants.  Wijsmann,  Pharm.  Zeit., 
xliii.  691;  abst.  Pharm.  Jmr.,  1899,  i.  337. 

Page  129.  Micro-chemical  recognition  of  Alkaloids.  L.  Erreva,  Pharm. 
Jour.,  xxiii.  48.  H.  B  a  r  t  h,  Pharm.  Jour.,  1898,  ii.  635  ;  1899,  i.  360. 
Vadam,  abst.  J.S.C.I.,  1897,  xvi.  165. 

Page  130.  Titration  of  Alkaloids.  L.  F.  Kebler,  Amer.  Jour.  Pharm., 
Ixvii.  499  ;  abst.  Chem.  News,  Ixxiii.  298.  H.  Brown,  Pharm.  Jour., 
XXV.  1180. 

Page  130.     Action  of  acids  on  Alkaloids.  A.  H.  A 1 1  e  n,  Chem.  News,  Ixvi.  259. 

Page  130.  Acidimetry  of  Alkaloids.  E.  Fali feres,  Compt.  rend.,  cxxix. 
110 ;  abst.  Pharm.  Jour.,  1899,  ii.  295. 

Page  131.  Volumetric  determination  of  Alkaloids.  E.  L6g  er,  Compt.  rend., 
cxv.  732;  abst.  J.S.C.I.,  1893,  xii.  470. 

Page  131.  Titration  of  Organic  Bases  with  methyl-orange.  G.  Lunge, 
Chem.  Ind.,  xvi.  490  ;  abst.  J.S.C.I.,  1894,  xiii.  667. 

Page  134.     Reagent  for  Alkaloids.    Orlow  &  Horst,  J.^.C.Z,  1901,  xx.  511. 

Page  135.  Tannates  of  Alkaloids  are  soluble  in  glycerin.  This  allows  of  a 
ready  separation  of  the  alkaloids  from  albumin.  (C.  Kippenberger, 
Analyst,  1895,  xx.  201.) 

Page  1 37.  G.  B  e  r  t  r  a  n  d  (abst.  Pharm.  Jour. ,  1899,  i.  503)  strongly  recom- 
mends Silico-tungstic  acid  as  a  precipitant  of  Alkaloids. 

Page  137.  Determination  of  Alkaloids  volumetrically  by  iodine  solution. 
0.  Linde,  ^rcA.  Pharm.,  1899,  ccxxxvii.  172;  abst.  J.C.S  ,  IxxvL 
ii.  534;  C.  Kippenberger,  Zeit.  anal.  Chem.,  1899,  xxxviii.  230, 
280  ;  absts.  J.C.S. ,  Ixxvi.  ii.  534,  584  ;  M.  Scholtz,  Zeit.  anal.  Chem., 
xxxviii.  278  ;  abst.  J.C.S.,  Ixxvi.  ii.  584. 

Page  138.  Delicacy  of  M  a r  m  e's  reagent  for  Alkaloids.  S.  V  e  r  v  e  n,  Ann. 
de  Pharm.,  xiii.  145  ;  abst.  Analyst,  1897,  xxii.  241. 

Page  138.  Alkaloidal  Periodides.  Determination  of  Alkaloids.  P  r  e  s  c  o  1 1 
and  Go r din,  ATner.  Jour.  Pharm.,  Ixx.  439;  Ixxi.  14,  18;  absts. 
Analyst,  1898,  xxiii.  324  ;  1899,  xxiv.  74,  75. 


ADDENDA.  58? 

Page  139.     Volumetric   determination   of  Alkaloids,     L.    B  a  r  t  h  e,    Compt. 

rend.,  cxv.  512  ;  abst.  Cliem.  News,  Ixvi.  223. 
Page  139.     Volumetric  determination  of  Alkaloids.     P.  C.  Plugge,  Compt. 

rend.,  cxv.  1012  ;  abst.  J.C.S.,  Ixiv.  ii.  199. 
Page  161.     Determination   of  Alkaloids.      Grandval  and   Lajoux,   J. 

Pharm.  et  Chim.,  xxviii.  99;  abst,  J.C.S.,  Ixiv.  ii.  608.     H.  A.  D. 

Jowett,  Pharm.  Jour.,  1899,  i.  377. 
Page  151.     Examination   of  decomposed  human  remains  of  Alkaloids.     0. 

Kippenberger,  Zeit.  anal.  Chem.,  xxxiv.  294  ;  abst.  J. O.S.,  1895, 

Ixviii.  ii.  465. 
Page  151.     Determination   of  Alkaloids.     K.    Dieterich,   Pharm.    Zeit.^ 

xliv.  242;  abst.  Pharm.  Jour.y  xxv.  962. 
Page  151.     Isolation  and  determination  of  Alkaloids.     C.  Kippenberger, 

Zeit.    anal.    Chem.,  xxxv.  10,407;  abst.  J.C.S.,  Ixx.  ii.    681,    682; 

Analyst,  xxi.  191.     F  a  rr  and  Wright,  Pharm.  Jour.,  1897,  i.  202. 
Page  151.   Alkaloidal  determinations.  G o r d i n  and  Prescott,  Amer.  Jour. 

Pharm.,  1899,  Ixxi.  514. 
Page  151.     Carbon  tetrachloride  as  a  solvent  in  the  estimation  of  Alkaloids. 

J.  Schindelmeiser,  Pharm.  Zeit.,  xlvi.  193  ;  abst.  Pharm.  Jour., 

1901,  1.  459. 
Page  151.     Determination  of  the  Solubility  of  Alkaloids.     R.  A.  Hatcher, 

Amer.  Jour.  Pharm.,  1902,  Ixxi  v.  134. 
Page  151.     Absorption  of  Alkaloids  by  Charcoal.     H.  Laval,  abst.  Pharm. 

Jour.,  1900,  ii.  213. 
Page  151.     Determination  of  Alkaloids.     Pharm.  Jour.,  1900,  ii.  286. 
Page  154.     Employment  of  Chloral  Hydrate  in  the  estimation  of  Alkaloids. 

E.    Schaer,  Zeit.    anal.   Chem.,   1899,   xxxviii.   469;  abst.  J.C.S., 

Ixxviii.  ii.  57. 
Page  154.     Detection   of   Alkaloids.     Hilger    and  Jan  sen,   Zeit.   anal. 

Chem.,  xxxvi.  344;  abst.  J.C.S.,  Ixxii.  ii.  436. 
Page  154.     Action  of    chloroform   and  other  solvents  on  Alkaloidal  salts. 

E.  Schaer,  Pharm.  Jour.,  1900,  i.  308. 
Page  160.     For  the  separation  of  Alkaloids  in  forensic  cases,  C.  Kippen- 
berger agitates  the  alkaloidal  solution,  first  with  sulphuric  acid  and 

chloroform  ;  then  with  caustic  soda  and  chloroform  ;  next  with  sodium 

bicarbonate  and  alcoholic  chloroform  ;  and  finally  saturates  with  sodium 

chloride  and  agitates  with  ether-chloroform,  which  last  treatment  re- 
moves Strophanthin.    {Zeit.  Awd.  Chem.,  1895,  p.  294;  abst.  Analyst, 

1895,  XX.  201.) 
Page  160.     Clau  s'  method  of  Tea-assay  is  valueless.     Compare  page  486. 
Page  161.     Lloyd's  process  is  stated  to  give  more  reliable  results  than 

any    other    rapid    method    of    Alkaloidal    Assay    (Nichols    and 

Norton,  Jour.  Anal,  and  Appl.    Chem.,  vi.    162;   abst.   J.S.C.I., 

1893,  vii.  68). 
Page  163.     History  of  the  constitution  of  the  Alkaloids.    A.  R.  L.  Dohme, 

Amer.  Jour.  Pharm.,  1900,  Ixxii.  9. 
Page  173.     New  test  for  Conine.     Van   Sen  us,  abst.  Analyst,  xv.  79. 
Page  174.     Preparation  and  properties  of  Ooniceine,  Conine,  etc.    Lellmann 

and  M tiller,  Berichte,  xxiii.  680;  abst.  J.C.S.,  Iviii.  802. 


588  ADDENDA. 

Page  175.     Detection    of   Conine    in    cases    of    poisoning.     Vitali    and 

Stropps,  abst.  Analyst,  1900,  xxv.  233. 
Page  176.     Volumetric   determination   of  Conine  and  Nicotine  in  the  same 

solution.     G.  H  e  u  t,  Arch,  de  Pharm.,  cexxxi.  376  ;  abst.  J.G.S.,  Ixiv. 

608. 
Page  176.     Assay  of  Con ium  Seed  or  Leaves.   H.  M.  Gordin,  Amer.   Jour. 

Pharm.y  1901,  Ixxiii.  217;  abst.  Analyst,  1901,  xxvi.  297. 
Page  179.     Chemistry  of  Tobacco.      Pictet  and  Rotschy,  Chem.  Zeit.^ 

xlvi.  118  ;  abst.  Pharm.  Jour.,  1901,  i.  424. 
Page  180.     One  c.c.  of  normal  hydrochloric  or  sulphuric  acid  is  neutralised 

by  0'162  gramme  of  Nicotine,    when  methyl-orange  is  used   as  the 

indicator. 
Page  181.     Detection  of  Nicotine.     J.   Schindelmeiser,  Pharm.  Centr., 

xl.  704  ;  abst.  Pharm.  Jour.^  1900,  i.  1. 
Page  182.     Determination    of    Ammonia    and    Nicotine    in    Tobacco.     V. 

Vedrbdi,  Zeit  anal.   Chem.,  1895;   abst.  Analyst,  1895,    xx.    255. 

R.  K  is  sling,  Zeit.  anal.  Chem.,  xxxiv.  731;  abst.  J.S  C.I.,  1896, 

XV.  300.     A.  Pezzolato,  abst.  J.C.S.,  Ix.  771. 
Page  182.     Determination  of  Nicotine  in  Tobacco.  C.  C.  Keller,  Chem.  Centr.^ 

1898,  ii.  388;  abst.    J.C.S.,  1899,  Ixxvi.  ii.  193.     J.  Foth,  Chem. 

Zeit.,  1901,  xxv.  610  ;  abst.  Pharm.  Jour.,  1900,  i.  747. 
Page  184.     Analysis    of   the    Tobacco-plant.        R.    J.    Davidson,    abst. 

J.C.S.,  Ixiv.  ii.  38. 
Page  184.     Three  new  Tobacco  Alkaloids.     Pictet  and  Rotschy,  Compt. 

rend.,  exxxii.  971. 
Page  189.     Determination   of  non-volatile    organic  acids  in   Tobacco.      R. 

Kis sling,  Chem.  Zeit.,  1899,  xxiii.  2  ;  abst.  J.C.S.,  1899,  Ixxvi.  ii. 

821. 
Page  190.     Composition  of  Tobaccos.     H.  B.  Cox,  Phnrm.  Jour.,  xxiv.  589. 
Page  190.     Paratfins  in  Tobacco-leaf.     Thorpe  and  Holmes,  Proe.  Chem. 

Soc,  1901,  xvii.  170  ;  abst.  J.S.C.I.,  1901,  xx.  758. 
Page  192.     Constituents  of  Tobacco-smoke.     H.   Thorns,  Pharm.    Centr., 

xl.  706  ;  abst.  Pharm.  Jour.,  1900,  i.  69. 
Page  192.     Composition  of  Tobacco-smoke.     A.    Gautier,    Compt.    rend.f 

cxv.  992  ;  abst.  J.C.S.,  Ixiv.  i.  226. 
Page  193.     Examination  of  Tobacco-extract.      J.    Pinette,    Chem.   Zeit., 

xvi.  178  ;  Analyst,  1892,  xvii.  178. 
Page  195.     Tincture   of  Lobelia.       J.    F.    Liver  see  ge,    Pharm.    Jour., 

Iv.  141. 
Page  198.     For  papers  on  the  Aconite  Alkaloids  by  Dunstan,  Umney, 

DunstanandCarr,  etc.,  see  Jour.  Chem.  Soc,  Ixi.  385,  393  ;  Ixiil 

443,  491,  991  ;  Ixv.  176,  290  ;  Ixvi.  308  ;  Ixx.  i.  192  ;  Ixx.  ii.  283  ; 

Ixxi.  35U.     Jour.  Soc.  Chem.  Ind.,  xi.  366.     Pharm.  Jour.,  xxii.  488  ; 

xxiii.  86,  625,  765,  1045;  xxiv.  581,  729,  735,  891,  910,  935;  xxv. 

773,  860,  928,  1117  ;  1896,  i.  121  ;  1898,  i.  323. 
Page  199.     Structure  of  various  Aconite   Roots.     A.    Goris,  abst.  Pharm. 

Jour.,  1901,  ii.  577. 
Page  202.     A  contribution  to  the  knowledge  of  Aconite  bases.     Dunstan 

and  Resid,J.C.S.,  1900,  Ixxvii.  45. 


ADDENDA.  589 

Page  207.     Formula  and  characters  of  Aconitine.     F.  B.  P  o  w  e  r,    Pharm. 

Jour.,  1900,  ii.  147. 
Page  226.     The  extraction,   composition,  and  properties  of  Atisine  and  its 

salts.     H.  A.  D.  J  o  w  e  1 1,  J.C.S.,  Ixix.  1518. 
Page  228.     Determination   of  Aconitine  in   aconite  extracts.     H.    Ecalle, 

Jour.  Pharm.  Chim.,  1901,  xiv.  97;  abst.  Analyst,  xxvi.  322;  abst. 

Pharm.  Jour.,  1901,  ii.  27. 
Page  236.     Cadaveric   Alkaloid    resembling    aconitine.     A.  Mecke,  Chem. 

Centr.,  1899,  ii.  256  ;  abst.  J.C.S.,  Ixxviii.  ii.  120. 
Pages  244  and  250.     0.  Hesse  has  shown  that  Hj^oscine  probably  has  the 

formula  C17H21NO4,   and  by  saponification   yields  the  base  o seine 

CgHigNOg,  and  not  pseudotropine  {Ann.  der  Chemie,  cclxxi.  100  ; 

abst.  Pharm.  Jour.,  [3],  xxiii.  221). 
Page  246.     According  to  S.  V  r  e  v  e  n,  Cadmium-Potassium  Iodide  gives  with 

Tropine,  in  slightly  acid  solutions,  a  cr3'stalline  precipitate  consisting 

of  well-formed  hexagonal  tables,  which  melt  above  200°  C.  to  a  clear 

liquid.     With  a  faintly  acid  solution  of  phosphomolybdic  acid,  tropine 

also  yields  a  yellowish  precipitate  of  microscopic  needles,  which  on 

warming  turns  green,  and  then  decomposes  without  melting.     These 

reactions     readily    distinguish    tropine    from    the     four    principal 

mydriatic  alkaloids  of  the  Solanacece,  which,  with  cadmium  potassium 

iodide,  give  either  amorphous  precipitates  or  crystalline  precipitates  of 

quite  different  appearance  ;    while  with  phosphomolybdic  acid  they 

yield  amorphous  ])recipitates  only. 
Page  247.     Some  new  Gold  Salts  of  the   Mydriatic  Alkaloids.     H.  A.  D. 

J  o  w  e  1 1,  /.  a  /S'. ,  Ixxi.  679. 
Page  247.     Notes  on  Solanace  us  Bases.     0.  Hesse,  Pharm.  Jour.,  1900,  i. 

117  ;  abst.  J.C.S.,  1900,  Ixxviii.  i.  50. 
Page  249.     Alkaloids    of   Hyoscyamus    muticus    and   Datura  Stramonium. 

Dun  stan  and  Brown,  J.C.S.,  1901,  Ixxix.  71. 
Page  250.  HyoscyamineSulphate,B2H2S04  +  2H20(5.P.,1898)  melts  at  206°  C. 
Page  251.     For    information    respecting  Apo-atropine,    Atropamine,    Bella- 

donine    and    Scopolamine,    see    E.    Schmidt     and    0.    Hesse, 

abst.  Pharm.  Jour.,  [3],  xxii.  1021 ;  xxiii.  221  ;  [4],  1899,  i.  383. 
Page  254.     Separation    of  Atropine  and  Hyoscyamine.     0.    Hesse,   abst. 

Pharm.  Jour.,  [3],  xxiii.  201. 
Page  258.     Test  for  distinguishing  Atropii.-e  from  Strychnine.     D.  Vitali, 

Chem.  Centr.,  1894,  ii.  816;  abst.  J.C.S.,  1895,  Ixviii.  ii.  467  ;  Zeit. 

anal.  Chem.,  xxxviii.  134;  abst.  J.S.G.L,  1899,  xviii.  404. 
Page  261.     Toxicological  detection  of  Atropine  and  its  allies.     Ciotto  and 

Spica,  abst.  J.C.S.,  Ix.  772. 
Page  261.     Detection   of  Atropine  in  forensic  cases.     P.  Sol  stein,   abst. 

Analyst,  1897,  xxii.  162. 
Page  262.     Note    on    the    B.  P.    standardisation    of    Belladonna.      J.    A. 

Dewhirst,  Pharm.  Jour.,  1900,  i,  358. 
Page  263.     Determination  of  Alkaloids  in  the  leaves  of  Datura  Stramonium* 

E.  Schmidt,  abst.  Pharm.  Jour.,  1900,  i  22. 
Page  264.     Assay  of  Belladonna  Root.     W.    A.  P  u  c  k  n  e  r,   abst.    Pharm. 

Jour.,  1898,  ii.  97.     E.  Dowzard,  Pharm.  Jaur.,  1899,  i.  309. 


590  ADDENDA. 

Page  265.     Official  processes  for  the  assay  of  Belladonna  and  its  preparations. 

F.  C.  J.  Bird,  Pharm.  Jour.,  1899,  i.  432  ;    1900,  i.  532,  690  ;  1900, 

ii.  195. 
Page  265.     Assay  of   Belladonna  Plasters.      C.    E.    Smith,   Amer.    Jour. 

Fharm.,   Ixx.    182.      F.    C.   J.  Bird,  abst.  Pharm.  Jour.,  1899,  ii. 

146. 
Page  265.     Assay  of  Belladonna  Root  and  its  solid  extract.     A.  W.  Clark, 

Amer.  Jour.  Pharm.,  1901,  Ixxiii.  22. 
Page  266.     Assay  of  liquid  extract  of  Belladonna.     H.  Wilson,    Pharm. 

Jour.,  1898,  i.  450. 
Page  269.     Official  extracts  of  Belladonna.     E.White,  Pharm.  Jour. ,  1901, 

i.  196  ;  Brit.  Pharmacopcsia,  1898,  p.  103. 
Page  270.     Constitution   of  Coca  Alkaloids.     W.  Garsed,  Pharm.  Jour., 

1901,  ii.  500,  519. 
Page  272.     Isolation  of  Cocaine  from  accompanying  alkaloids.     Einhorn 

and  Will  Stat  ter,  abst.  J.C.S.,  Ixvi.  i.  478. 
Page  274.     Test   for  Cocaine.     Scharges,   Chem.   Centr.,   1893,   ii.    888; 

abst.  J.C.S.,  Ixvi.  ii.  127. 
Page  274.     Properties    of   Eucaine    and    Cocaine.       G.     Vulpius,    abst. 

J.S.C.I.,  1896,  XV.  679,  745.   P.  S  il  e  x,  abst.  J.S.C.L,  1897,  xvi.  631. 
Page  274.     Reactions  of  Cocaine.    J.  C.  Stead,  Pharm.  Jour.,  xxii.  902.    A. 

Kub  orne,  Pharm.  Centr.,  xxxiii.  411  ;  abst.  J.S.C.L,  1893,  xii.  380. 
Page  274.     Detection  of  Cocaine  in  poisoning  cases.     H.  W.    Glasenap, 

Chem.  Centr.,  1894,  ii.  220  ;  abst.  J.C.S.,  1895,  Ixviii.  ii.  336. 
Page  27i.     For  the  detection  of  Cocaine,  A.  Kub  orne,  Jun.  {Chem.  News, 

Ixvii.   254),  recommends  that  1  c.c.  of  nitric  acid  (1'42  sp.  gr.)  be 

added  to   the  substance   in    a  porcelain   dish,  and  the  liquid  evap- 
orated at  100°  C.     When  cold,  a  drop  of  alcoholic  potash  is  added. 

No  colour  is  produced  in  the  cold  (distinction  from  atropine),    but 

when  heated  on  the  water-bath  an  intense  violet  coloration  is  suddenly 

produced. 
Page  274.     A  new  test  for  Cocaine.     G.  L.  Schaf  er,  J.  Amer.  Chem.  Sac, 

1899,  xxi.  634  ;  abst.  J.C.S.,  Ixxvi.  ii.  715. 
Page  274.     The  Chromic  Acid  test  for  Cocaine.     G.   L.  S  chafer,  Pharm. 

Jour.,  1899,  ii.  66. 
Pages  277  and  283.     Reactions  of  Cocaine  and  Ecgouine.     D.  Y  itali,  abst. 

J.C.S.,\x.  1561. 
Page  280.     Characters  of  Cocaine  hydrochloride.     Paul  and  C  o  w  n  1  e  y, 

Pharm.  Jour.,  1898,  i.  586. 
Page  280.     Test  for  the  purity  of  Cocaine  salts.     G.   L.  Schafer;    A.  J. 

C  o  wn  1  e  y  ;  Pharm.  Jour.,  1899,  i.  336. 
Page  280.     A  new  Alkaloid  in  Coca  leaves.     G.  L.  S  c  h  a  f  er,  abst.  Pharm. 

Jour.,  1899,  i.  359. 
Page  280.     Maclagan's  ammonia  test  for  the  purity  of  Cocaine  hydro- 
chloride.    See  absts.  Pharm.  Jour.,  1898,  i.  449,  473  ;  1898,  ii.  26  ; 

1899,  i.  431. 
Page  281.     Estimation    of   Cocaine.    Garsed  and  Collie,  J.C.S.,   1901, 

Ixxix.   675  ;  abst.  Pharm.  Jour.,  1901,  i.  553  ;  Pharm.  Jour.,  1901,  ii. 

222,  254 ;  abst.  Analyst,  1901,  xxvi.  322. 


ADDENDA.  591 

Page  284.     Identification    and    properties    of   o-    and    )8-Eucaine.      C.    L. 

Parsons,  Jour.  Amtr.  Chem.  Soc,  1901,  xxiii.  885;  abst.  Analyst, 

1902,  xxvii.  123. 
Page  287.     Properties  of  Ben zoyl-pseudotro pine  and  its  salts.     Pharm.  Jour., 

[3],  xxiii.  241. 
Page  292.     Assay  of  Coca  leaves.    "W.  R.  Lamar,  Amer.  Jour.  Pharm.,  1901, 

Ixxiii.  125. 
Page  293.     Assay  of  fluid  extract  of  Coca.     C.  T.  K  i  n  g  s  1  e  y,  Amer.  Jour. 

Pharm.,  1896,  p.  609  ;  abst.  Analyst,  1897,  xxii.  77. 
Page  293.     The  author  was  indebted  to  Mr  D.  B.  Dott  for  perusal  and 

correction  of  the  section  on  Opium  Alkaloids. 
Page  295.     Assay  of  Sanguinaria  and  its  preparations.     C.  H.  La  Wall, 

Amer.  Jour.  Pharm.,  1896,  p.  305. 
Page  295.     Reactions  of  Chelidonine  with  phenols.     J.  A.  Battandier, 

Compt.  rend.,  cxx.  270  ;  abst.  J.C.S.,  1895,  Ixviii.  ii.  336. 
Page  295.     Alkaloids  of  Sanguinaria,  Eschscholtzia  and  Glaucium  Luteum. 

R.  Fischer,  abst.  Pharm.  Jour.,  1901,  ii.  385. 
Page  295.     Alkaloids  of  Chelidonium.    Schmidt,  abst.  Phorm.  Jour.,  1901, 

ii.  361.     Win  tern,  abst.  Pharm.  Jour.,  1901,  ii.  40.^.. 
Page  295.     Characters  of   Alkaloids  of  Chelidonium.     G.    B  o  1 1,    Pharm. 

Jour.,  1901,  ii.  317. 
Page  296.     Alkaloids  of  Bocconia  cordata.     M u r r i  1 1  and  Schotterbeck, 

Pharm.  Jour.,  1900,  ii.  34. 
Page  300.     Solubility  of  Morphine  and   Narcotine.     E.  L.  Patch,  Amer. 

Jour.  Pharm.,  1898,  p.  553. 
Page  305.     Detection  of  Alkaloids  by  the  Stas-Otto  method.     R.  Otto, 

Arch,  de  Pharm.,  ccxxxiv.  317  ;  abst.  J.G.S.,  Ixx.  ii.  508. 
Page  309.     Researches  on  Morphine.     Schry  ver  and  Lees,  J".C.*S'.,  1900, 

Ixxvii.  1024  ;  Ixxix.  563  ;  abst.  Pharm.  Jour.,  1901,  i.  713. 
Page  312.     Derivatives  of  Morphine.     (Merck's  Report,  1898.)    Pharm.  Zeit., 

xliv.  117  ;  abst.  J.S.C.L,  1899,  xviii.  395. 
Page  312.     Properties  of  Dionine,     L.  Hesse,  Pharm.  Centr.,  xl.  1  ;  abst. 

Analyst,  1899,  xxiv.  128. 
Page  312.     Crystalline  characters  of  Morphine  Hydrochloride.   F.  B.  P  o  w  e  r, 

Pharm.  Jour.,  1900,  ii.  151. 
Page  313.     Colour-tests  for  Morphine.    G.  B  r  u  y  1  a  n  t  s,  J.  Pharm.  et  Chim., 

May  1st,  1895  ;  abst.  Pharm.  Jour.,  xxv.  1123. 
Page  313.     Reactions  for  Morphine.     G.    Bruylants,   Bull.   Soc.    Chim., 

xiii.  497  ;  abst.  J.C.S.,  Ixx.  ii.  132. 
Page  315.    The  Furfural  reactions  of  Alkaloids.     N.  W  e  n  d  e  r,  Chem.  Zeit., 

xvii.  950;  abst.  J S.C.I.,  1893,  xii.  869. 
Page  316.     The  determination   of  Morphine.     C.    Kippenber ger,  Zeit. 

anal.  Chem.,  xxxv.  421  ;  abst.  Analyst,  xxii.  42. 
Page  316.     The  determination  of  Alkaloids  in  Narcotic  extracts.       J.  H. 

Schmidt,  Chem.  Zeit.,  xvi.  1275  ;  abst.  J.S.C.L,  1893,  xii.  470. 
Page  316.     Titration  of  Morphine.     Cannepin  and  van  E  i  j  k.  Bull.  Soc. 

Chim.,  ix.  437  ;  abst.  J.C.S.,  Ixiv.  ii.  607. 
Page  316.     Determination  of  Morphine  in  Opium.     M  on  temartini  and 

Trasciatti,  abat.  Analyst,  1899,  xxiv.  264  ;  abst.  J.C.S.,  1899,  Ixxvi. 


692  ADDENDA. 

ii.  619.    G  0  r  d  i  n  and  P  r  e  s  c  o  1 1,  Arch.  Pharm.,  ccxxxvii.  380  ;  abst. 

J.C.S.,  1899,  Ixxvi.  ii.  714. 
Page  316.     Extraction  of  Morphine  with  immiscible  solvents.     Puckner, 

J.  Amer.  Chem.  Soc,  1901,  xxiii.  470. 
Pago  317.     Ferricyanide    test  for   Morphine.     Schaer,  Arch,   de  Pharm.y 

ccxxxiv.  348  ;  abst.  Pharm.  Jour.,  1896,  ii.  61. 
Page  317.     Detection  and  determination  of  Morphine.     F.   Wirt  hie,  abst. 

J.S.C.L,  1901,  XX.  511  ;  abst.  Analyst,  1901,  xxvi.  236. 
Page  317.     Determination     of    Morpliine.       Orlow    and     Horst,     abst. 

J.S.C.L,  1901,  XX.  511. 
Page  320.     Heroin  (Di-acetyl  morphine).    Harnack,  abst.   Pharm.  Jour., 

1899,  ii.  65. 
Page  820.     Dionine,  a  new  morphine  derivative.     L.Hesse,  abst.  J.S.CL, 

1899,  xviii.  295. 

Page  321.     Examination    of   Codeine.     Tambach  and  Henke,    Pharm. 

Centr.,  xxxviii.  159  ;  abst.  Analyst,  xxii.  219. 
Page  321.     On    the    Pharmacopceial    tests    for    Codeine.      F.    B.    Power, 

Pharm.  Jour.,  1900,  ii.  149. 
Page  323.     Separation  of  Codeine  and  Morphine.     L.  Fouquet,  J.  Pharm. 

et  Ghim.,  xvii.  49  ;  abst.  J.S.C.L,  1897,  xvi.  159. 
Page  325.     Laudanosine,   its    production    and    constitution.     Pictet    and 

Athanascscu,  Ber.,  xxxiii.  2346  ;  Pharm.  Jour. ,  1900,  ii.  572. 
Page  326.     According  to  E.  Levoy,  thermo-chemical  measurements  show 

that  Narceine  is  the  weakest  of  the  opium  bases. 
Page  327.     Reactions  for  Narceine  and  Papaverine.     C.  Kippenberger, 

Zeit.  anal.  Chem.,  1895,  p.  £94  ;  abst.  Analyst,  1895,  xx.  201. 
Page  331.     The  chemistry  of  Thebaine.     M.  F  r  e  u  n  d,  BerichU,  1897,  p.  11  ; 

abst.  J.C.S.,  Ixviii.  i.  117  ;  Ixxii.  i.  494. 
Page  333.     Amount  of  Morphine  in  dried  Opium.     E.  Dowzard,  Pharm. 

Jour.,  1900,  ii.  99. 
Page  340.     Determination    of   starch   and    strontium    sulphate    in    Opium. 

K  e  b  1  e  r  and  L  a  W  a  1 1,  Amer.  Jour.  Pharm. ,  1897,  p.  244. 
Page  342.     Assay  of  0]num  and  its  preparations.     Grandval  and  L  a  j  o  u  x, 

J.  Pharm.  et  Chim.,  1897,  p.  153  ;  abst.  J.S.C.L,  1897,  xvi.  265.     G. 

Looff,  Apoth.  Zeit.,  1896,  ii.  192;  abst.  Analyst,  xxi.  163.     F.  X. 

Moerk,  Amer.  Jour.  Pharm.,   1877,  page  344.     E    J.   Millard, 

Pharm.  Jour.,  xxiv.  831.     D.  B.  Dott,  Pharm.  Jour.,  1892,  p.  7J6  ; 

1894,  p.  847.     G.  Coull,  Pharm.  Jour.,  1894,  p.  954;  1895,  ii.  75. 

G  o  r  d  i  n  and  Present  t.  Arch.  Pharm. ,  ccxxxvii.  380  ;  abst.  J.  S.  C.  L , 

1900,  xix.  784.  W.  R.  Lama r,  Am^r.  Jour.  Pharm.,  1900,  Ixxii.  36. 
W.  Stoeder,  Pharm.  Cevtr.,  xlii.  518  ;  abst.  Pharm.  Jour.,  1902,  i.  1. 
H.  Thorns,  Chem.  Centr.,  1898,  ii.  136;  abst.  J.S.C.L,  1899, 
Ixxvi.  ii.  194. 

Page  350.     Manufacture  of  Chinese  Extract  of  Opium.     J.  Calvert,  Pharm. 

Record,  xxx.  822  ;  abst.  Pharm.  Jour.,  1901,  i.  27. 
Page  350.     Liquid  Extract  of  Opium  [P.P.,  1898)  contains  075  gramme  of 

morphine  per  100  c.c,  and  has  a  specific  gravity  between  0'985  and 

0-995. 
Page  351.    Assay  of  Laudanum.  L.  F,  Kebler,  Amer.  J.  Pharm.,  1893,  p.  209. 


ADDENDA.  593 

Page  356.     Tests  for  Morphine  in  forensic  cases.    D.  L.  D  a  v  o  1 1,  Jun. ,  Amer. 

Chem.  Jour.,  xvi.  799  ;  abst.  Analyst,  xx.  38.     J.  B.  N  ag  el  voort, 

Amer.  Jour.  Fharm.,  1896,  p.  374. 
Page  358.     Detection    of  poisoning  by  Opium.      Mercke,   abst.    J.O.S., 

Ixxviii.  ii.  180. 
Page  361.     Nux  Vomica  preparations  are  said  to  contain  a  minute  trace  of 

Copper. 
Page  363.     Liquor  Strychninse  Hydrochloridi  (B. P.,  1898).     Martindale, 

Lunan,  and  others,  Fharm.  Jour.,  1898,  1.  587;  1898,  11.  19,  43, 

67  ;  1899,  i.  120. 
Page  363.     Water  of  crystallisation   of  Strychnine   Hydrochloride.     D.  B. 

Dott,  Pharm.  Jour.,  1899,  i.  58  ;  W.  H.  Martindal  e,  ^&^c^.,  p.  120. 
Page  363.     Interaction  of  Strychnine  Hydrochloride  and  Potassium  Arsenate. 

J.  R.  H  ill,  Fharm.  Jour.,  1900,  i.  184. 
Page  363.     Action  of  Chloroform  on  Strychnine  salts.     J.  R.  Hill,  Pharm. 

Jour.,  1900,  i.  185. 
Page  363.     Strychnine  Hydrochloride,  BHCI  +  2H2O,  is  official  in  the  Brit. 

Pharmacoposia   of   1898.     "W.    H.    Martindale  regards  the  com- 
mercial salt  as  a  combination  or  mixture  of  an  equal  number  of  mole- 
cules of  BHC1,2H20  and  BHCl,liH20,containing7'84  percent,  of  water. 
Page  364.     Alkaloidal    content    of    Strychnine  salts.     W.    Duncan;    G. 

Coull  ;  Fharm.  Jour.,  xxii.  843,  846. 
Page  364.     According  to  D.  B.  Bott  (Fharm.  Jour.,  [3],  xxiii.   197),  the 

solubility  of  Strychnine  Hydrochloride  in  cold  water  is  1  in  35. 
Page  364.     Detection   of  Strychnine  in  forensic  cases,    A.    S.    Cushman, 

Chem.  Centr.,  1894,  ii.  461  ;  abst.  J.C.S.,  1895,  Ixviii.  ii.  542. 
Page  364.     Behaviour  of  Iodoform  and  Chloroform  with  Strychnine.     P.  F. 

Trowbridge,  abst.  J.G.S.,  Ixxviii.  i.  187. 
Page  367.     The  following  Alkaloids  are  not  precipitated  by  potassium  ferro- 

cyanide  : — atropine,  codeine,  emetine,  narceine,  sparteine,  "  veratrine." 
Page  367.     Separation  of  Strychnine   from  Brucine.     W.  Stoeder,  Chem. 

Centr.,  1899,  i.  506  ;  abst.  J.C.S.,  Ixxvi.  ii.  715. 
Page  367.     Determination   of  Strychnine.      Farr  and  Wright,   Pharm. 

Jour.,  1900,  ii.  82,  140. 
Page  368.     Action  of  sulphuric  acid  on  Strychnine.     Bailey  and  Lange, 

Amer.  Jour.  Fharm.,  1898,  p.  18. 
Page  368.     Examination  of  the  Oxidation-test  for  Strychnine.     Mason  and 

Bowman,  Amer.  Chem.  J(mr.,xyi.  824 ;  abst.  J.S.C.I.,  1895,  xiv.  313. 
Page  368.     Detection    of    Strychnine.      H.    Beckurts,    Arch.    Fharm.', 

abst.  Fharm.  Jour.,  xxiv.  2. 
Page  383.     Colour-reactions  of  Brucine.     P.  Pich  ard,  Compt.  rend.,  cxxiii. 

590 ;  abst.  Analyst,  1897,  xxii.  47. 
Page  384.     The  Brucine  and  Strychnine  in  nux  vomica  seeds  exist  in  separate 

cells.     Sau  van,  J.  Fharm.  et  Chim.,  vi.  i.  497  ;  abst.  Fharm.  Jour., 

XXV.  1090. 
Page  385.     Assay  of  Nux  Vomica  and  its  Preparations.     See  Brit.  Fharmxi- 

copoiia,  1898,  pp.  117,  118.    Also  F.  C.  J.  Bird,  Fharm.  Jour.,  1900, 

ii.  214,  574.     E.  R.  Squibb,  J.  Amer.  Chem.  Soc,  1899,  xxi.  351. 

F.  H.  A 1  cock,  Pharm.  Jour.,  1900,  i.  174. 
VOL.  III.  PART  II.  2  P 


594  ADDENDA. 

Page  386.     Determination  of  Nux  Vomica  Alkaloids.    C.  C.  Keller,  Apoth. 

Zeit.,  viii.  542  ;  abst.  J.S.O.L,  1894,  xiii.  1105. 
Page  388.     Most  specimens  of  Curare  contain  methyl-strychnine,  which  is  one 

of  the  most  active  ingredients.     See  E.  Anquetil,    abst.   Pharm. 

Jour.,  xxiii.  624. 
Page  391.     Materia    Medica   of    Cinchona     Bark.       Pharm.    Jour.,     1901, 

i.  552. 
Page  391.     Formation  of  the   Cinchona  Alkaloids.      J.    C.    Lotsy,    abst. 

Pharm.  Jour.,  1900,  ii.  689  ;  abst.  J.S.O.L,  1901,  xx.  498. 
Page  396.     Per-bromides  of  Cinchona  Alkaloids.     A.  Christensen,  Chem. 

Centr.,  Ixxii.  1377  ;  abst.  Pharm.  Jour.,  1901,  ii.  313. 
Page  396.     Test  for  Cinchona  Alkaloids.      Jaworowski,   /.    Pharm.   et 

Chim.,  1896,  p.  553  ;  abst.  J.C.S.,  Ixx.  ii.  629. 
Page  401.     Modifications  of  the  Thalleioquin  reaction.     J.    Ducommon, 

Chem.  Zeit.,  1895,  p.  214  ;  abst.  Analyst,  xx.  234.    F.  S.  H  y  d  e,  Arrier. 

Chem.  Jour.,  xix.  331  ;  abst.  Analyst,  1897,  xxii.  266. 
Page  401.     A  reaction  for  Quinine.     C.  Carrez,  J.  Pharm.  et  Chim.,  1896, 

p.  253  ;  abst.  J.C.S.,  Ixx.  ii.  584. 
Page  402.     Determination   of  Quinine.      L.    Bar  the,    Compt.   rend,.,   cxv. 

1085;  abst.  J.S.C.I.,  1893,  xii.  380. 
Page  403.     Titration  of  Quinine.     L.  F.  Kebler,  Amer.  Chem.  Jour.,  1895, 

xvii.  822  ;  abst.  J.C.S.,  Ixx.  ii.  551.     A.  H.  Allen,  Analyst,  xxi.  85. 
Page  403.     The  basicity  of  Quinine.     D,  &  D.  L.  Howard,  Pharm.  Jour., 

1898,  i.  154. 
Page  408.     The   testing  of  Quinine   Sulphate.     M.   Kubli,    Chem.    Centr. y 

1895,  ii.  1058  ;  abst.  J.C.S.,  Ixx.  ii.  550  ;  Ixxii.  ii.  168.     0.  Hesse, 

Arch,  de  Pharm.,  ccxxxiv.  195  ;  abst.  J.C.S.,  Ixx.  ii.  550. 
Page  408.     A  test  for  the   purity  of  Quinine   Salts.     J.  de   Vrij;  abst. 

J.S.C.I.,  1897,  xvi.  165. 
Page  408.     Tests  for  Quinine.     T.  G.    "Worm ley,  Amer.  Jour.  Pharm. ^ 

Ixvi.  561  ;  abst.  Pharm.  Jour.,  xxv.  542. 
Page  418.    Acid  Quinine  Hydrochloride (-B.P.,1898) contains B(HC1)2+3H20. 
Page  418.     Interaction  of  Quinine  Hydrochloride  and  Caffeine.     Paul  and 

C  own  ley,  Pharm.  Jour.,  1900,  i.  438. 
Page  419.     Quinine   Arsenate   exists  in  the  form  of  fine,   colourless,  silky 

needles.    G  u  i  g  u  e  s  obtained  it  by  adding  a  dilute  solution  of  arsenic 

acid  to  hydrated  Quinine,  suspending  in   water  and   gently  warming 

until  distinctly  acid.      The  warm  solution  was  then  exactly  neutralised 

with  dilute    ammonia,    the    liquid    allowed    to    cool,   and    the    salt 

crystallised. 
Page  419.     Notes  on  Quinine  Acetate.    J.  R.  Hi  1 1,  Pharm.  Jour.,  1900,  i.  416. 
Page  419.     Quinine  Glycerophosphate.     P  r  u  n  i  e  r,  Jour,  de  Pharm. ,  xii.  272  ; 

abst.  Pharm.  Jour.,  1900,  ii.  439. 
Page  423.    The   Tincture  and  "Wine  of  Quinine  (P.P.,   1898)  are    prepared 

with  quinine  hydrochloride  instead  of  with  the  sulphate. 
Page  424.     Therapeutic  value  of  Quinine  Esters.    0  v  e  r  1  a  c  h,  Pharm.  Zeit., 

xlvl.  694;  abst.  Pharm.  Jour.,  1901,  ii.  449. 
Page  429.     Action  of  Bromine  on  Cinchonidine.      J.    G  a  1  i  m  a  r  d,    Chem. 

Centr.,  Ixx.  401 ;  abst.  Pharm.  Jour.,  1901,  i.  485. 


ADDENDA.  595 

Page  431.  Examination  of  commercial  samples  of  Cinchonine.  Jun  g  f  1  e  i  s  ch 
and  Leger,  Compt.  rend.,  cxxxii.  828  ;  abst.  J.S.C.L,  1901,  xx.  499. 

Page  431.  Action  of  sulphuric  acid  upon  Cinchonine.  Z.  H.  Skraup,  abst. 
J". ^. a/.,  1901,  XX.  499. 

Page  431.  Preparation  of  Allocinchonine.  0.  J.  Hlavnicka,  abst.  J.S.C.I.t 
1901,  XX.  499. 

Page  432.  Assay  of  Liquid  Extract  of  Cinchona.  F.  H.  Alcock,  Pharm. 
Jour.,  1901,  ii.  90  ;  abst.  Analyst,  xxvi.  323. 

Page  445.  Assay  of  Tincture  of  Cinchona.  Farr  and  Wright,  Pharm. 
Jour.,  xxiii.  248. 

Page  445.  Valuation  of  Cinchona  Extract.  M.  L.  Hulsebosch,  Chem. 
Centr.,  1896,  i.  141  ;  abst.  J.C.S.,  Ixx.  ii.  682. 

Page  449.  Determination  of  the  Alkaloids  in  Cinchona  Bark.  M.  L. 
Hulsebosch,  Pharm.  Centr. ,  xiv. 289  ;  abst.  J.S. C.I. ,  1896,  xv.  887. 
W.Haubensack,  Pharm.  Centr. ,  xxxii.  294 ;  abst.  J.  ,S.  C.  /. ,  1 892,  xi. 
779.  J.  H.  Schmidt,  Chem.  Zeit.,  xvi.  307  ;  abst.  J.S.C.L,  1893,  xii. 
467.  W.  Lenz,  Zeit.  anal.  Chem.,  xxxviii,  141;  abst.  J.S.C.L, 
1899,  xviii.  408.  H.  E  kxo  os,  Arch.  de.  Pharm.,  1898,  p.  328  ;  abst. 
Amer.  Jour.  Pharm. ,  April,  1 899.  F.  M  y  1 1  e  n  a  e  r  e,  /.  >S'.  C. 7. ,  1902, 
p.  721. 

Page  449.  B.  A.  Yan  Ketel  suggests  the  following  method  of  Cinchona- 
assay,  which  is  applicable  to  all  the  fixed  alkaloids  soluble  in  ether. 
Four  grammes  of  the  powdered  bark  is  mixed  with  two  grammes  of 
powdered  lime,  5  c.c.  of  solution  of  ammonia  added,  and  boiled  on 
a  water-bath  under  a  reflux  condenser  for  half-an-hour  with  100  o.c.  of 
ether.  The  solution  is  then  filtered,  the  insoluble  matter  washed  with 
80  C.C.  of  ether,  and  the  filtrate  shaken  well  with  10  c.c.  of  10  per  cent, 
hydrochloric  acid.  The  acid  liquid  is  separated,  and  the  ethereal 
solution  well  washed  with  water,  which  is  added  to  the  acid.  The  acid 
solution  is  then  shaken  with  excess  of  caustic  soda  solution  and  ether. 
The  extraction  with  ether  is  repeated,  the  ether  evaporated,  and  the 
alkaloids  weighed.  The  alkaloids  left  on  evaporation  may  also  be  titrated. 

Page  461.  Morphology  and  Pharmacognosy  of  Berberis  vulgaris.  G. 
Pinchbeck,  Pharm.  Joiir. ,  1 901,  i.  262. 

Page  461.     Materia  Medica  oi  Berberis.     Pharm.  Jour.,  1901,  ii.  402, 

Page  461.  Determination  of  Berberine.  H.  M.  G  o  r  d  i  n,  abst.  Pharm. 
Jour.,  1901,  ii.  599. 

Page  464.  Composition  of  Berberine  Phosphate.  F.  S  h  e  d  d  e  n,  PhoA'm. 
Jour.,  1900,  ii.  89. 

Page  467.  Constitution  of  Hydrastine  and  its  derivatives.  Frits  ch, 
Liebig's  Annalen,  cclxxxvi.  21  ;  abst.  Pharm.  Jour.,  xxv.  1193. 

Page  467.  Properties  of  the  Alkaloids  of  Hydrastis  Canadensis.  K.  v  o  n 
Bunge,  Chem.  Centr.,  1895,  i.  1173  ;  abst.  J.C.S.,  Ixx.  ii.  492. 

Page  467.  The  Chemistry  of  Hydrastine  and  its  salts.  Freund  and 
Dormeyer,  Berichte,  xxiv.  2730,  3164;  abst.  J.C.S.,  Ix.  1518; 
Ixii.  i.  223. 

Page  467.  Assay  of  Hydrastis.  0.  Schreiber,  abst.  Pharm.  Jour.,  1901, 
ii.  273  ;  Gordin  ani  Prescott,  Jour.  Amer.  Chem.  Soc,  xxi.  732  ; 
abst.  Phann.  Jour.,  1899,  ii.  445  ;  1900,  i.  8. 


596  ADDENDA. 

Page  468.  Reactions  of  Hydrastine  and  other  alkaloids.  D.  V  i  t  a  1  i, 
abst.  J.C.S.,  Ixii.  i.  755. 

Page  474.  In  Tea,  the  Cutfeine  exists  largely  as  a  glucoside  or  in  some  other 
complex  form. 

Page  475.  According  to  Tasilly,  Hydrated  Caffeine  does  not  part  with  all 
its  combined  water  even  when  heated  to  150°  C,  at  which  temperature 
the  alkaloid  begins  to  volatilise. 

Page  475.  Loss  of  weight  of  Caffeine  when  heated.  F.  B.  P  o  w  e  r,  Fharm, 
Jour.,  1900,  ii.  148. 

Page  483.  Caffeine  Ethyl-iodide  is  obtained  by  heating  caffeine  with  excess  of 
ethyl-iodide  in  a  sealed  tube  for  twenty  hours  at  a  temperature  of  160  ta 
170°  C.  It  is  crystallised  from  alcohol.  It  melts  at  182  to  183°  C. ,  and  is 
soluble  in  water  and  alcohol,  but  insoluble  in  ether,  benzol,  chloroform, 
petroleum-ether,  and  carbon  disulphide. 

Page  483.  Characters  of  Caffeine  Citrate,  B.P.  F.  B.  P  o  w  e  r,  Pharm.  Jour.^ 
1900,  ii.  148. 

Page  489.  Determination  of  Caffeine.  E.  Tassily,  Ball.  Soc.  Chim.^ 
xvii.  596,  706,  761  ;  abst.  J.S.C.L,  1897,  xvi.  697,  831.  M.  Gomberg, 
ATner.  Chem.  Jour.,  xviii.  331;  abst.  Analyst,  1896,  xxi.  193.  A. 
Delacour,  J.  Pharm.  et  Chim.,  iv.  490  ;  abst.  Analyst,  1897,  xxii.  76. 

Page  489.  Determination  of  Caffeine.  Forst  er  and  Reic  hel  m  an  n,  and 
Hilger  and  Juckenack,  Chem.  Centr.,  1897,  [1],  775;  abst. 
Analyst,  1897,  xxii.  189,238.  G.L.  Spencer,  Amer.  Chem.  Jour.,x\x. 
279  ;  sihst.  J.C.S.,  Ix.  134,  964.  C.  C.  Keller,  Chem.  Zeit.,  xxi. 
102  ;  abst.  J.S.C.L,  1897,  xvi.  568.  W.  A.  Puckner,  Avier.  Chem. 
Jour. ,  xviii.  978  ;  abst.  J.  S.  C.I. ,  1896,  xv.  925.  P  e  t  i  t  and  T  e  r  r  a  t, 
Bttll.  Soc.  Chim.,lS96,-p.  811 ;  Sihst.  Analyst,  1896,  p.  232.  E.Georges, 
J.  Pharm.  et  Chim.,  xvi.  58  ;  abst.  Analyst,  1896,  xxi.  232.  F.  Vite, 
Chem.  Centr.,  1890,  ii.  274;  abst.  J.G.S.,  Ix.  372.  Trillich  and 
Gockel,  Zeit.  f.  IJntersuch.,  1898,  p.  101  ;  abst.  Analyst,  1898,  xxiii. 
179.  Guillot,  Apoth.  Zeit.,  viii.  132;  abst.  J.C.S.,\yiiv.  ii.  608. 
C.  H.  La  Wall,  Amer.  Jour.  Pharm.,  1897,  p.  350  ;  abst.  Analyst^ 
1897,  xxii.  238. 

Page  490.  Determination  of  Caffeine  in  Tea.  N.  V.  Sokoloff,  abst. 
J.O.S.,  Ixiv.  ii.  352.  Ke liner,  Forschungs-berichte,  iv.  88;  abst 
Pharm.  Jour.,  1897,  ii.  83. 

Page  490.  Determination  of  Caffeine  in  Tea.  E.  H.  G  a  n  e  {Jour.  Soc.  Chem. 
Ind.,  1896,  page  95)  states  that,  after  a  trial  of  several  processes,  he 
found  the  author's  method  to  give  the  best  and  most  concordant 
results.  A  comparison  of  the  results  obtained  by  Gane  with  the 
methods  of  Paul  and  C  o  w  n  1  e  y  and  of  the  author  shows  that  the 
latter  process  gives  identical  or  higher  yields  of  caffeine  than  the  former, 
whilst  the  alkaloid  is  obtained  in  a  state  of  great  purity.  Gane  regards 
the  author's  method  as  less  tedious  and  more  accurate  than  other 
methods.  He  prefers  in  every  case  to  boil  the  tea  with  600  c.c.  of 
water  in  the  first  place,  and  to  add  the  lead  acetate  before  filtration. 
This  modification  is  at  least  necessary  in  the  case  of  "gunpowder  "  and 
certain  other  teas,  as  was  pointed  out  by  the  a  u  t  h  o  r  (page  490),  owing 
to  the  slow  filtration  of  the  liquid. 


ADDENDA.  597 

Page  493.     Theobromine  crystallised  from  aqueous  solutions  may  be  dried 

without  loss  at  a  temperature  of  50°  C.     The  base  is  not  hygroscopic, 

differing  largely  from  Caffeine  in  this  respect  ;  and,  according  to  Th. 

Paul,  its  solubility  in  water  at  18°  C.  is  1  in  3282. 
Page  493.     The  Examination  of  Theobromine.     M.  Francois,  J.  Pharm. 

et  Ghim.,  vii.  521  ;  abst.  Analyst,  1898,  xxiii.  213. 
Page  493.     Theobromine  and  its  homologues.     B  runner,  and  B  runner 

and  Leins,  abst.  J.S.C.L,  1898,  xvii.  78,  946. 
Page  496.     Determination     and    separation     of    the    Alkaloids    of    Cocoa. 

Brunner  and  Leins,  Chem.  Centr.,  1898,  p.  512;  abst.  J.S.C.L^ 

1898,  xvii.  961. 
Page  496.     Determination   of  Theobromine    in   Cocoa,    etc.     Hilger  and 

Eminger,    Forsch.   Ber.,   1894,   p.  292;  abst.  J.C.S.,  Ixviii.  642. 

L.    Maupy,    J.    Pharm.   et  Ghim.,    1897,   v.    329;    abst.   J.S.C.L, 

xvi.  641.     P.  Siiss,  Zeit.  anal.  Chem.,  xxxii.  67;  abst.  J.C.S.,  Ixiv. 

198. 
Page  496.     W.  E.  Ku  n  ze  (Zeit anal.  Chem.,  xxxiii.  1  ;  abst.  Analyst,  1894, 

page  194)  has  proposed  the  following  method  for  the  determination  and 

separation  of  the  Alkaloids  of  Cocoa  : — 
For  the  estimation  of  the  total  alkaloids,  ten  grammes  of  the  cocoa  is 
boiled  for  twenty  minutes  with  about  150  c.c.  of  five  per  cent,  sulphuric 
acid,  filtered,  and  the  residue  thoroughly  washed  with  boiling  water.  The 
alkaloids  are  precipitated  from  the  filtrate  by  a  large  excess  of  a  nitric  acid 
solution  of  sodium  phosphomolybdate,  and  the  liquid  kept  warm  for  twenty- 
four  hours.  It  is  then  filtered,  the  precipitate  washed  with  the  dilute 
sulphuric  acid,  and  at  once  decomposed  by  baryta-water,  the  excess  of 
barium  being  precipitated  by  passing  carbon  dioxide  through  the  liquid. 
The  liquid  and  precipitate  are  together  evaporated  to  dryness,  dried,  and 
exhausted  with  boiling  chloroform  under  a  reflux  condenser.  On  evapora- 
tion, the  filtered  chloroform  solution  leaves  the  alkaloids  almost  perfectly 
pure,  and  containing  only  a  trace  of  ash. 

For  the  separation  of  the  caffeine  and  theobromine  thus  obtained,  the 
theobromine  is  converted  into  its  insoluble  silver  salt.  (Caffeine  does  not 
form  a  similar  compound.)  For  this  purpose,  the  mixed  alkaloids  are  dis- 
solved in  ammonia,  a  considerable  excess  of  silver  nitrate  added,  and  the 
liquid  boiled  down  to  a  very  small  bulk,  and  until  all  free  ammonia  is  expelled. 
The  crystalline  precipitate  of  theobromine-silver  salt  (C7H7AgN402)  is 
collected,  well  washed  with  boiling  water,  dried,  ignited,  and  the  residual 
silver  weighed.  If  a  known  measure  of  standard  silver  nitrate  be  employed, 
the  amount  of  theobromine  precipitated  may  be  deduced  from  the  excess  of 
silver  contained  in  the  filtrate  as  determined  by  V  o  1  h  a  r  d's  method.  After 
the  titration,  the  alkaloids  may  be  readily  extracted  from  the  precipitate 
and  filtrate,  and  tested  as  to  their  purity,  etc. 

Kunze's  paper  contains  a  valuable  resum^  and  criticism  of  the  methods 
hitherto  employed  for  the  separation  of  the  cocoa  alkaloids,  and  the  sub- 
stantial accuracy  of  his  process  is  confirmed  by  analytical  data. 
Page  499.     Materia  Medica  of  Tea.     Pharm.  Jour.,  1901,  ii.  661. 
Page  604.     Percentage  of  Caffeine  in  Chinese  Teas.   J.  K  o  c  h  s,  abst.  Pharm. 

Jov/r.,  1900,  ii.  637. 


598  ADDENDA. 

Page  504.     Analysis  of  Tea.     Domergue  and  Nicolas,  J.   Pharm.    et 

Chim.,  XXV.  302 ;  abst.  J.C.S.,  Ixii.  ii.  926. 
Page  506.     Detection  of  Extracted  Tea.    W.  A.  Tichomirow,  abst.  Ghem. 

News,  Ixvii.  196. 
Page  509.     New  Adulterant  of  Tea.     Delaite  and  Lonay,  Bull.  A,  Beige 

Chim.,  xi.  13  ;  abst.  J.S.C.I.,  1897,  xvi.  700. 
Page  510.     Mineral  matter  in  Caper  Tea.     Analyst,  1899,  xxiv.  333, 
Page  516.     The  analysis  of  China  Teas.     P.  Dvorkovitz,  abst.  Jour.  Soc, 

Chem.  Ind.,  x.  276. 
Page  518.     In  employing  Eder's  process  for  the  determination  of  Tannin 

in  Tea,  the  excess  of  copper  may  be  determined  by  ferrocyanide. 

Maltscheffsky,  J.  Pharm.  CMm.,  xxil  270  ;  abst  J.C.S.,  Ix.  132. 
Page  520.     The  composition  of  Caper  Tea.     C.  E  s  t  c  o  u  r  t,  Analyst,  xxiv.  30. 

J.  White,  ibid.,  p.  117. 
Page  522.     Chinese  Tea  and  certain  of  its  substitutes.    E.  Collin,  Jou/r.  de 

Pharm.,  xi.  15,  52  ;  abst.  Pharm.  Jour.,  1900,  i.  91. 
Page  526.     The  composition  of  Mate  or  Paraguay  Tea.     H.  K  u  n  z-K  r  a  u  s  e, 

Arch,   de  Pharm.,   ccxxxi.    613;   abst,    Pharm.    Jour.,    xxiv.    442. 

Mc Ken d rick  and  Harris,  Pharm.  Jour.,  1890,  ii.  52. 
Page  526.     Contributions    to    the    study   of    Mate.     P.    Macquaire,    J. 

Pharm.  et  CMm.,  1896,  p.  346  ;  abst.  Analyst,  xxii.  18.     B.  A.  Katz, 

Zeit.  Nahr.  Uhtersuch.,  x.  364  ;  abst.  Analyst,  1897,  xxii.  41. 
Page  526.     The  word  "mate"  is  used  adjectively,   referring   to  the  gourd 

from  which  the  scalding  infusion  is  sucked  through  the  bombilla— that 

is,  a  tube  having  a  bulb  at  one  end.     We  should,  therefore,  always 

say  "  Yerba  Mate,"  the  gourd-plant. 
Page  526.     Materia  Medica  of  Mate  Tea.     Pharm.  Jour.,  1901,  ii.  661. 
Page  526.     Mate  Tea.    W.  F.  Buist,  Pharm.  Jour.,  1901,  i.  155. 
Page  527.     The  composition  of  Oatha  edulis.     E.  Collin,  Pharm.   Jour,, 

xxiv.  345. 
Page  527.     The  following  analyses  of  "  Coffee-Tea"  (coffee  leaves)  are  from 

the  Lancet,  5th  August,  1893  : — 


Whole  Leaf. 

Small  Broken  Leaf. 

Caffeine, 

2-66 

3-20 

Tannin, 

7-14 

6-66 

Extract, 

39-45 

34-40 

Moisture, 

7-60 

7-69 

Ash, 

6-10 

5-50 

Page  528.  Proportion  of  various  constituents  of  Coffee.  Herfeldt  and 
Stutzer,  Zeit.  angew.  Chem.,  1895,  p.  469  ;  abst.  J.C.S. ,  Ixx.  ii.  63. 

Page  528.  Proportion  of  water  in  raw  Coffee.  B.  Niederstadt,  Forsch. 
Ber.,  1897,  p.  141  ;  abst.  Analyst,  1897,  xxii.  322. 

Page  528.  A  new  Alkaloid  of  Coffee  (Cotfearine).  Fors  ter  and  Reich  el- 
man  n,  Pharm.  Zeit.,  xlii.  309  ;  abst.  Pharm  Jour.,  1897,  ii.  84.  P. 
Paladin o,  abst.  ATialyst,  1895,  xx.  141. 

Page  528.  Composition  of  Coffee  from  the  Grand  Comoro  Island.  G. 
Bert  rand,  Compt.  rend.,  cxxxii.  162,  164;  abst.  Analyst,  xxvi. 
188. 


ADDENDA.  599 

Page  528.     Studies  on  new  descriptions  of  Coffee.     T.  F.  H  a  n  a  n  s  e  k,  abst. 

Analyst,  xxiv.  284. 
Page  530.      Alteration  in  composition  of  Coffee  during  roasting.      H  i  1  g  e  r 

and  Juckenack,   Forsch.  Ber.,iy.  119;  abst.  Analyst,  1897,  xxii. 

287.     H.  Jaeckle,  Zeit.  f.  Untersitch.,  1898,  p.  457;  abst.  Analyst, 

1898,  xxiii.  264. 

Page  533.      The  Carboliydrates  of  the  Coffee-berry.     E.  E.  E  w  e  1 1,  Amer. 

Chem.  Jour.,  xiv.  473  ;  abst.  J.S.C.L,  1893,  xii.  614. 
Page  533.      A  Ptomaine  in  Coffee.     S.  Bein,    Zeit.    angew.    Chem.,    1898, 

p.  658  ;  abst.  Analyst,  1899,  xxiv.  36. 
Page  534.     Glazed  Coflfee-berries.      E.  H  a  n  a  u  s  e  k,  abst.  Analyst,  xxiv.  36. 
Page  535.     Exhausted  Coffee-berries.     P.  E.   Ham  el  Roos,  ah^t.  Analyst, 

xvi.  160. 
Page  535.     Analysis  of  a  spurious  roasted  Coffee.     M.  M  alj  ea  n,  /.  Pharm,. 

et  Chim.,  1896,  p.  352  ;  abst.  Analyst,  1897,  xxii.  17. 
Page  535.     E.    Bertarelli   calls   attention   to  the  adulteration  of  roasted 

coffee-beans  by  the  practice  of  pouring  over  them  a  boiling  aqueous 

solution  of  borax,  whereby  an  increase  of  about  12  per  cent,  in  their 

weight  is  produced,  without  their  original  hardness  being  impaired. 

Genuine  roasted  coffee  does  not  usually  contain  more  than  about  3  per 

cent,  of  water.     Borax  should  be  looked  for  in  cases  where  4  per  cent. 

or  more  of  water  is  found. 
Page  536.     Note  on  a  sample  of  artificial  Coffee-berries.     C.   H.    C  r  i  b  b. 

Analyst,  xxvii.  114. 
Page  538.    Adulterations  of  Coffee.      G.  y^ ixtz,  Zeit.  f.   Untersuch.,  1898, 
p.  248  ;  abst.  Analyst,  xxiii.  209.     Pear  main  and  Moor,  Analyst, 

XX.  176. 
Page  538.     Variations  in  the  composition  of  Chicory.     B.  Dyer,  Analyst, 

xxiii.  226. 
Page  538.     Sugar  in  roasted  Chicory.     E.  G.  Clayton,  Analyst,  xx.  12. 
Page  538.     Composition  and  Analysis  of  Chicory.     J.  Wolff,  abst.  Analyst^ 

1899,  xxiv.  261. 

Page  539.     Determination     of    Caramel    in     Coffee    roasted    with    sugar. 

Fresenius  and  G r ii n h u t,  Zeit.  anal.  Chem. ,  xxxvi.  225  ;  abst. 

Analyst,  1897,  xxii.  285. 
Page  539.     The  analysis  of  Chicory.     A.  Ru  f  f  i  n,  Chem.  Ccntr.,  1898,  p.  1147  j 

abst.  J.S.C.L,  1898,  xvii.  699. 
Page  544.     Composition   of    Dandelion   root  (Taraxacum).     L.    E.    Sayre» 

Amer.  Jour.  Pharm.,  Ixix.  543  ;  abst.  Analyst,  xxiii.  10. 
Page  545.     Composition  of  the  Ash  of  Coffee.     F.  W.  Dafert,  abst.  J.C.S., 

Ixvi.  ii.  -207. 
Page  547.     Composition  of ' '  coffee-palace "  Coffee  Infusions.    E.  G.  Clayton, 

Analyst,  xxii.  172. 
Page  553.     Composition  and  Analysis  of  Coffee  Extracts.    Moor  and  Priest, 

Analyst,  1899,  xxiv.  281. 
Page  554.      Composition  of  Kola-nuts.     Uffelmann  and  Bomer,    Zeit. 

angew.  Chem.,  xxiii.  710;  abst.  Analyst,  1895,  xx.   42.     Knox  and 

Prescott,  Amor.  Chem.  Jour.,xx.  34  ;  abst.  Analyst,  1897,  xxii.  131. 

E.  K  neb  el,  Apoth.   Zeit..  vii.  112;  abst.  J.S.C.L,  1892,  xi.  545. 


600  ADDENDA. 

.  K.  Dieter  icli,  Apoth.  Zeit.,  xi.  810  ;  abst.V.^.C.7.,  1897,  xvi.  160. 

P.  Carles,  J.  Pharm.  et  Chim.,  xvi.  104  ;  Ann.  der   Chimie,   xviii. 

345  ;  abst.  Analyst,  1896,  xxi.  265,  292. 
Page  554.     False  Kola-nuts.     J.  H.  Hart,  Pharm.  Jour.,  1898,  i.  184. 
Page  554.     Kolanin  and   Coconin,    the   Glucosides   of  the    Kola-nut.        C. 

Schweitzer,  Pharm.  Zeit,  xliii.  380,  389;  abst.    Pharm.    Jour.y 

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